G Protein Pathway Suppressor 2 (GPS2) Is a Transcriptional Corepressor Important for Estrogen Receptor α-mediated Transcriptional Regulation
G Protein Pathway Suppressor 2 (GPS2) Is a Transcriptional Corepressor Important for Estrogen Receptor α-mediated Transcriptional Regulation
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DOI：
10.1074/jbc.m109.062109
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发表时间：
2009-12-25
影响因子：
4.8
通讯作者：
Kao, Hung-Ying
中科院分区：
文献类型：
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作者：
Cheng, Xiwen;Kao, Hung-Ying
我们已经确定G蛋白抑制因子2(GPS2)是SMRT辅阻遏子复合体的稳定成分。GPS2有效地抑制基础转录，抑制结构域被映射到维甲酸和甲状腺激素受体(SMRT)相互作用的N端沉默介体。GPS2的敲除被取消，而过表达则增强了SMRT介导的抑制活性。SMRT复合体参与4-羟基-三苯氧胺(4OHT)介导的雌激素受体α(ERα)介导的基因抑制。我们发现，4OHT以动态方式将SMRT和GPS2招募到ERα靶基因PS2的启动子上。出乎意料的是，我们还发现雌二醇(E2)促进了SMRT复合体的启动子招募。虽然GPS2基因的敲除抑制了4OHT介导的抑制作用，但它增强了E2诱导的一个报告基因和几个内源性ERα靶基因的表达，包括PS2、细胞周期蛋白D1(CCND1)、孕激素受体(PR)和c-myc。最后，我们发现siRNA缺失GPS2或SMRT可以促进MCF-7乳腺癌细胞的增殖。因此，我们得出结论，GPS2是SMRT复合体的一个组成部分，对ERα对配体依赖的基因调控很重要，也是MCF-7细胞增殖的抑制因子。
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 (ER alpha). We show that 4OHT recruits SMRT and GPS2 to the promoter of pS2, an ER alpha 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 ER alpha 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 ER alpha and a suppressor for MCF-7 cell proliferation.