The regulation of gene expression in response to ER stress
thesisposted on 31.01.2017, 16:32 authored by Abdulsalam Elfowiris
A disruption in endoplasmic reticulum (ER) homeostasis can lead to ER stress and the accumulation of misfolded proteins, which has been implicated with the development of diabetes and many other diseases. In reaction to this the cell mounts an adaptive response termed the unfolded protein response (UPR) to improve cell survival during ER stress through the activation of three ER stress transducers PERK, ATF6 and IRE1. However, in case of unresolved ER stress, the UPR can triggers apoptosis pathway. UPR adaptive response is intended to restore ER homeostasis through decreasing ER load, increasing ER folding capacity and increasing ER associated degradation. At the centre of the UPR is transmembrane protein PERK which upon the phosphorylation of eIF2α leads to represses of global protein synthesis coextensive with preferential translation of mRNAs, such as activating transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP). In this study, I investigated the molecular mechanisms of translational repression in response to ER stress in MIN6 cells and how ATF protein expression is up-regulated in response to ER stress. In conclusion, I provide evidence that the eIF2α is likely responsible for the repression of protein synthesis in the presence of ER stress and that the induction of ATF4 expression in response to ER stress is dependent on its transcriptional upregulation. PERK mediated eIF2α phosphorylation is not required for increased ATF4 expression in MIN6 cells in response to ER stress. However, in MEFs, the PERK/eIF2α pathway is required for ATF4 protein expression, IRE1-XBP1 pathway is also required for ATF4 expression which might be time dependent, and protein synthesis is essential for induction of ATF4 expression in response of ER stress. Further investigations into how ATF4 expression is up-regulated in response to ER stress may extend our understanding to develop new therapies to protect ER from stress.