cb200092v_si_001.xls (238 kB)
Similarities and Differences between Two Modes of Antagonism of the Thyroid Hormone Receptor
dataset
posted on 2011-10-21, 00:00 authored by Prabodh Sadana, Jong Yeon Hwang, Ramy R. Attia, Leggy
A. Arnold, Geoffrey Neale, R. Kiplin GuyThyroid hormone (T3) mediates diverse physiological functions including
growth, differentiation, and energy homeostasis through the thyroid
hormone receptors (TR). The TR binds DNA at specific recognition sequences
in the promoter regions of their target genes known as the thyroid
hormone response elements (TREs). Gene expression at TREs regulated
by TRs is mediated by coregulator recruitment to the DNA bound receptor.
This TR–coregulator interaction controls transcription of target
genes by multiple mechanisms including covalent histone modifications
and chromatin remodeling. Our previous studies identified a β-aminoketone
as a potent inhibitor of the TR-coactivator interaction. We describe
here the activity of one of these inhibitors in modulating effects
of T3 signaling in comparison to an established ligand-competitive
inhibitor of TR, NH-3. The β-aminoketone was found to reverse
thyroid hormone induced gene expression by inhibiting coactivator
recruitment at target gene promoters, thereby regulating downstream
effects of thyroid hormone. While mimicking the downstream effects
of NH-3 at the molecular level, the β-aminoketone affects only
a subset of the thyroid responsive signaling network. Thus antagonists
directed to the coregulator binding site have distinct pharmacological
properties relative to ligand-based antagonists and may provide complementary
activity in vivo.