Regulation of androgen receptor activity by the nuclear receptor corepressor SMRT
Regulation of androgen receptor activity by the nuclear receptor corepressor SMRT
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DOI：
10.1074/jbc.m206374200
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发表时间：
2003-02-14
影响因子：
4.8
通讯作者：
Chen, JD
中科院分区：
文献类型：
--
作者：
Liao, GQ;Chen, LY;Chen, JD
雄激素受体 (AR) 是一种激素调节的转录因子，可介导多种生物过程，包括性分化、精子发生和前列腺癌进展。 AR 和核受体超家族其他成员的转录活性受到共调节蛋白的调节。在这项研究中，我们研究了类维生素A和甲状腺激素受体（SMRT）沉默介体对AR转录活性的调节。我们发现AR具有内在的转录抑制活性，并且AR直接与SMRT相互作用。 AR 上的一个相互作用表面被映射到配体结合域，并且 DNA 结合/铰链区的存在增强了这种相互作用。 SMRT 上的结合表面被映射到 C 端 ID2 区域，ID2 辅阻遏基序的突变会抑制相互作用。 SMRT 的过表达抑制 AR 的二氢睾酮依赖性反式激活，并进一步抑制抗雄激素氟他胺介导的 AR 活性抑制。我们提供的证据表明，SMRT 介导的 AR 活性抑制机制涉及抑制 AR N/C 相互作用以及与 p160 共激活因子的竞争。我们的数据证实了 SMRT 在调节 AR 转录活性中的重要作用。
Androgen receptor (AR) is a hormone-regulated transcription factor that mediates a wide array of biological processes including sexual differentiation, spermatogenesis, and prostate cancer progression. The transcriptional activity of AR and other members of the nuclear receptor superfamily are modulated by coregulatory proteins. In this study, we have investigated the regulation of AR transcriptional activity by the silencing mediator for retinoid and thyroid hormone receptors (SMRT). We found that AR possesses an intrinsic transcriptional repression activity, and AR interacts directly with SMRT. One interacting surface on AR is mapped to the ligand-binding domain, and the presence of a DNA binding/hinge region enhances this interaction. The binding surface on SMRT is mapped to the C-terminal ID2 region, and mutation in the ID2 corepressor motif inhibits the interaction. Overexpression of SMRT inhibits dihydrotestosterone-dependent transactivation by AR and further suppresses the antiandrogen flutamide-mediated inhibition of AR activity. We provide evidence to suggest that the mechanisms of SMRT-mediated inhibition of AR activity involves inhibition of AR N/C interaction and competition with the p160 coactivator. Our data establish a significant role of SMRT in modulating AR transcriptional activity.