Progesterone Receptor B Recruits a Repressor Complex to a Half-PRE Site of the Estrogen Receptor α Gene Promoter
Progesterone Receptor B Recruits a Repressor Complex to a Half-PRE Site of the Estrogen Receptor α Gene Promoter
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DOI：
10.1210/me.2008-0267
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发表时间：
2009-04-01
影响因子：
--
通讯作者：
Ando, S.
中科院分区：
文献类型：
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作者：
De Amicis, F.;Zupo, S.;Ando, S.
在本研究中，我们证明，孕激素受体（PR）-B亚型在乳腺癌细胞中的水平升高诱导雌激素受体（ER）α mRNA和蛋白质含量的下调，导致伴随的雌激素调节基因胰岛素受体底物1，细胞周期蛋白D1和pS2的抑制，解决了PR/PR-B对ER α基因转录的具体影响。ER α基因启动子活性被PR-B过表达显著抑制。启动子分析显示，一个转录响应区域包含一个半孕酮反应元件（PRE）的网站位于-1757至-1752 bp。半PRE突变下调PR/PR-B过表达诱导的效应。此外，染色质免疫沉淀分析显示PR结合ER α调控区，包括半PRE网站的增加，并募集一个辅阻遏物复合物含有核受体辅阻遏物（NCoR），但不沉默类维生素A和甲状腺激素受体和DAX1的介体，伴随着组蛋白H4的低乙酰化和RNA聚合酶II的位移。此外，NCoR消融研究表明，由于PR-B过表达对ER α蛋白和mRNA的下调作用，NCoR参与其中。我们还证明了在MCF-7细胞中观察到的ER α调节依赖于PR-B表达，因为PR-B敲低部分消除了雌激素刺激后ER α水平的反馈抑制。我们的研究为过表达的PR-B能够主动抑制ER α基因表达的机制提供了证据。（分子内分泌学23：454 - 465，2009）
In the present study, we demonstrate that elevated levels of the progesterone receptor (PR)-B isoform in breast cancer cells induces down-regulation of estrogen receptor (ER) alpha mRNA and protein content, causing concomitant repression of the estrogen-regulated genes insulin receptor substrate 1, cyclin D1, and pS2, addressing a specific effect of PR/PR-B on ER alpha gene transcription. ER alpha gene promoter activity was drastically inhibited by PR-B overexpression. Promoter analysis revealed a transcriptionally responsive region containing a half-progesterone response element (PRE) site located at - 1757 bp to - 1752 bp. Mutation of the half-PRE down-regulated the effect induced by PR/PR-B overexpression. Moreover chromatin immunoprecipitation analyses revealed an increase of PR bound to the ER alpha-regulatory region encompassing the half-PRE site, and the recruitment of a corepressor complex containing nuclear receptor corepressor (NCoR) but not silencing mediator of retinoid and thyroid hormone receptor and DAX1, concomitantly with hypoacetylation of histone H4 and displacement of RNA polymerase II. Furthermore, NCoR ablation studies demonstrated the crucial involvement of NCoR in the down-regulatory effects due to PR-B overexpression on ER alpha protein and mRNA. We also demonstrated that the ER alpha regulation observed in MCF-7 cells depended on PR-B expression because PR-B knockdown partially abrogates the feedback inhibition of ER alpha levels after estrogenic stimulus. Our study provides evidence for a mechanism by which overexpressed PR-B is able to actively repress ER alpha gene expression. (Molecular Endocrinology 23: 454-465, 2009)