G Protein Pathway Suppressor 2 (GPS2) Is a Transcriptional Corepressor Important for Estrogen Receptor α-mediated Transcriptional Regulation

Xiwen Cheng,Hung-Ying Kao

doi:10.1074/jbc.m109.062109

Xiwen Cheng, Hung-Ying Kao

Open Access

https://doi.org/10.1074/jbc.m109.062109

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Abstract

We have identified G protein suppressor 2 (GPS2) as a stable component of the SMRT corepressor complexes. GPS2 potently represses basal transcription, with the repression domain mapped to the N-terminal silencing mediator of retinoic acid and thyroid hormone receptor (SMRT)-interacting domain. Knockdown of GPS2 abrogates, whereas overexpression potentiates, SMRT-mediated repression activity. The SMRT complexes are involved in 4-hydroxyl-tamoxifen (4OHT)-mediated gene repression by estrogen receptor alpha (ERalpha). We show that 4OHT recruits SMRT and GPS2 to the promoter of pS2, an ERalpha target gene, in a dynamic manner. Unexpectedly, we also found that estradiol (E2) promotes promoter recruitment of the SMRT complexes. While knockdown of GPS2 compromised 4OHT-mediated repression, it enhanced E2-induced expression of a reporter gene and several endogenous ERalpha target genes, including pS2, cyclin D1 (CCND1), progesterone receptor (PR), and c-MYC. Finally, we show that depletion of GPS2 or SMRT by siRNA promotes cell proliferation in MCF-7 breast cancer cells. Thus, we concluded that GPS2 is an integral component of the SMRT complexes, important for ligand-dependent gene regulations by ERalpha and a suppressor for MCF-7 cell proliferation.

Highlights

We further examined the association between G protein suppressor 2 (GPS2) and SMRT by epitope-tagged overexpression and co-immunoprecipitation experiments
We found Because SMRT is implicated in TAM-mediated transcripthat GPS2 co-precipitated with class I HDACs, HDAC1, and tional repression by ER␣, we examined whether GPS2 is
We demonstrate that GPS2 is a stable component of the SMRT corepressor complexes

Summary

Introduction

Our data suggested that GPS2 is an important component of SMRT corepressor complexes and functionally involved in agonist- or antagonist-regulated ER␣-mediated transcription. These results support a model in which cells, we co-transfected FLAG-GPS2 and HA-tagged class I or GPS2 is a functional component of SMRT corepressor complex class II HDAC expression plasmids and performed immuno- and that GPS2 is important for SMRT-mediated repression. GPS2 in ER␣-mediated transcription in response to antagonist treatment, we carried out ChIP assays and determined the temporal pattern of the recruitment of components of SMRT complexes on the pS2 promoter (Fig. 8) with treatment of 4OHT.

Results

Conclusion