BRCA1 Counteracts Progesterone Action by Ubiquitination Leading to Progesterone Receptor Degradation and Epigenetic Silencing of Target Promoters
BRCA1 Counteracts Progesterone Action by Ubiquitination Leading to Progesterone Receptor Degradation and Epigenetic Silencing of Target Promoters
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DOI：
10.1158/0008-5472.can-10-3670
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发表时间：
2011-05-01
期刊：
影响因子：
11.2
通讯作者：
Beato, Miguel
中科院分区：
文献类型：
--
作者：
Calvo, Veronica;Beato, Miguel
BRCA 1基因的生殖系突变增加了女性患乳腺癌的风险，但这种联系的确切机制基础仍然不确定。一种解释乳腺组织特异性的流行假说认为BRCA 1与卵巢激素雌激素和孕激素的作用有关。鉴于孕酮与正常乳腺发育和乳腺癌形成的相关性，我们在PR阳性乳腺癌细胞系T47 D中寻找BRCA 1和孕酮受体（PR）之间的功能关系。在这里，我们报告说，BRCA 1抑制PR的转录活性至少有2种机制，涉及BRCA 1的E3泛素连接酶活性。首先，BRCA 1对PR的细胞水平有直接影响，因此，通过促进其配体非依赖性和依赖性降解，对PR募集到靶启动子的程度有直接影响。通过体外和体内实验，我们发现BRCA 1/BARD 1可能是E3泛素连接酶的主要成员，在激素缺乏的情况下，它负责PR的泛素化和降解。第二，在激素处理细胞后，BRCA 1/BARD 1复合物通过与PR相互作用被募集到PR靶基因的免疫应答区域，影响单泛素化组蛋白H2 A的局部水平，并有助于这些启动子的表观遗传沉默。我们的研究结果表明BRCA 1/BARD 1和PR活性之间的联系可能有助于解释为什么BRCA 1中的宿主突变在优先提高乳腺癌风险方面发挥组织特异性。Cancer Res; 71（9）; 3422-31. (C)2011年AACR。
Germ-line mutations in the BRCA1 gene increase the risk of breast cancer in women, but the precise mechanistic basis for this connection remains uncertain. One popular hypothesis to explain breast tissue specificity postulates a link between BRCA1 and the action of the ovarian hormones estrogen and progesterone. Given the relevance of progesterone for normal mammary development and breast cancer formation, we searched for a functional relationship between BRCA1 and progesterone receptor (PR) in the PR-positive breast cancer cell line T47D. Here, we report that BRCA1 inhibits the transcriptional activity of PR by at least 2 mechanisms involving the E3 ubiquitin ligase activity of BRCA1. First, BRCA1 has a direct effect on the cellular level of PR and, hence, on the extent of PR recruitment to target promoters through the promotion of its ligand-independent and -dependent degradation. Through in vitro and in vivo assays, we found that BRCA1/BARD1 may be the main E3 ubiquitin ligase responsible for ubiquitination and degradation of PR in the absence of hormone. Second, after hormone treatment of cells, the BRCA1/BARD1 complex is recruited via interaction with PR to the hormone-responsive regions of PR target genes, affecting local levels of monoubiquitinated histone H2A and contributing to epigenetic silencing of these promoters. The connections between BRCA1/BARD1 and PR activity suggested by our findings may help explain why host mutations in BRCA1 exert a tissue specificity in preferentially elevating the risk of breast cancer. Cancer Res; 71(9); 3422-31. (C) 2011 AACR.