Differential SERM Effects on Corepressor Binding Dictate ERα Activityin Vivo

Paul Webb, Phuong Nguyen, Peter J. Kushner
2002 Journal of Biological Chemistry  
Selective estrogen receptor modulators (SERMs) show differential effects upon ER␣ activation function 1 (AF-1). Tamoxifen allows strong ER␣ AF-1 activity, whereas raloxifene allows less and ICI 182,780 (ICI) allows none. Here, we show that blockade of corepressor histone deacetylase (HDAC) activity reverses the differential inhibitory effect of SERMs upon AF-1 activity in MCF-7 cells. This suggests that differential SERM repression of AF-1 involves HDAC-dependent corepressors. Consistent with
more » ... . Consistent with this, ICI and raloxifene are more potent than tamoxifen in promoting ER␣-dependent sequestration of progesterone receptor-associated corepressors. Moreover, ICI and raloxifene are more efficient than tamoxifen in promoting ER␣ binding to the corepressor N-CoR in vivo and in vitro. An ER␣ mutation (537X) that increases N-CoR binding in the presence of all SERMs blocks AF-1 activity. An ER␣ mutation (L379R) that decreases N-CoR binding increases AF-1 activity in the presence of ICI and raloxifene and reverses the effect of the 537X mutation. The 537X and L379R mutations also alter the ligand preference of ER␣ action at AP-1 sites and C3 complement, an action that also involves AF-1. Together, our results suggest that differential SERM effects on corepressor binding can explain differences in SERM effects on ER␣ activity. We propose a model for differential effects of SERMs on N-CoR binding. Estrogen signaling is mediated by two estrogen receptors (ER␣ and ER␤), 1 which are conditional transcription factors (1-3). In the best understood pathway of ER action, the ERs bind specific estrogen response elements (EREs) in the promoter of estrogen-regulated genes and activate transcription
doi:10.1074/jbc.m208501200 pmid:12482846 fatcat:sabprmvi2bbcjld3zx2bgvpkui