The androgen receptor recruits nuclear receptor CoRepressor (N-CoR) in the presence of mifepristone via its N and C termini revealing a novel molecular mechanism for androgen receptor antagonists
The androgen receptor recruits nuclear receptor CoRepressor (N-CoR) in the presence of mifepristone via its N and C termini revealing a novel molecular mechanism for androgen receptor antagonists
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DOI：
10.1074/jbc.m408972200
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发表时间：
2005-02-25
影响因子：
4.8
通讯作者：
Hollenberg, AN
中科院分区：
文献类型：
--
作者：
Hodgson, MC;Astapova, I;Hollenberg, AN
雄激素受体（AR）在激动剂配体存在的情况下，通过募集转录辅激活因子激活靶基因表达，但最近的研究表明，核辅抑制因子NCoR和SMRT的过表达会减弱这种激动剂介导的AR激活。本研究利用NCoR siRNA和染色质免疫沉淀证明内源性NCoR被募集到并抑制双氢睾酮（DHT）配体AR。此外，本研究还表明，在DHT存在时，NCoR和共激活物会竞争AR。目前用于前列腺癌治疗的AR拮抗剂，如比卡鲁胺，也可以介导NCoR募集，但纳米摩尔浓度的米非司酮（RU486）具有显著增强AR-NCoR相互作用的独特能力。ru486配体AR与NCoR的c端片段相互作用，这种相互作用是由NCoR中存在的两个最多的c端核受体相互作用域（rid）介导的。值得注意的是，除了AR配体结合域外，这种相互作用还需要AR N端。诱变研究表明，ar介导的NCoR募集的n端表面与tau5和介导激动剂诱导的n - c端相互作用的FXXLF基序不同。综上所述，这些数据表明NCoR是AR的生理调节剂，并揭示了AR拮抗的新机制，可能用于开发更有效的AR拮抗剂。
The androgen receptor (AR) activates target gene expression in the presence of agonist ligands via the recruitment of transcriptional coactivators, but recent work shows that overexpression of the nuclear corepressors NCoR and SMRT attenuates this agonist-mediated AR activation. Here we demonstrate using NCoR siRNA and chromatin immunoprecipitation that endogenous NCoR is recruited to and represses the dihydrotestosterone (DHT)-liganded AR. Furthermore this study shows that NCoR and coactivators compete for AR in the presence of DHT. AR antagonists such as bicalutamide that are currently in use for prostate cancer treatment can also mediate NCoR recruitment, but mifepristone (RU486) at nanomolar concentrations is unique in its ability to markedly enhance the AR-NCoR interaction. The RU486-liganded AR interacted with a C-terminal fragment of NCoR, and this interaction was mediated by the two most C-terminal nuclear receptor interacting domains (RIDs) present in NCoR. Significantly, in addition to the AR ligand binding domain, the AR N terminus was also required for this interaction. Mutagenesis studies demonstrate that the N-terminal surface of the AR-mediating NCoR recruitment was distinct from tau5 and from the FXXLF motif that mediates agonist-induced N-C-terminal interaction. Taken together these data demonstrate that NCoR is a physiological regulator of the AR and reveal a new mechanism for AR antagonism that may be exploited for the development of more potent AR antagonists.