Ubiquitination and proteasome-mediated degradation of BRCA1 and BARD1 during steroidogenesis in human ovarian granulosa cells
Ubiquitination and proteasome-mediated degradation of BRCA1 and BARD1 during steroidogenesis in human ovarian granulosa cells
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DOI：
10.1210/me.2006-0188
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发表时间：
2007-03-01
影响因子：
--
通讯作者：
Hu, Yanfen
中科院分区：
文献类型：
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作者：
Lu, Yunzhe;Amleh, Asma;Hu, Yanfen
BRCA1的种系突变使女性易患早发性、家族性乳腺癌和卵巢癌。然而，BRCA1的表达并不局限于乳腺和卵巢上皮细胞。例如，卵巢BRCA1在卵巢颗粒细胞中表达丰富，而卵巢颗粒细胞负责绝经前妇女卵巢雌激素的产生。此外，最近的组织培养和动物研究表明BRCA1在卵巢颗粒细胞中的功能作用。尽管已知BRCA1水平在卵泡发育和类固醇形成过程中有显著波动，但颗粒细胞中BRCA1表达调控的机制仍有待阐明。本研究表明，泛素-蛋白酶体降解途径在卵巢颗粒细胞中BRCA1及其伴侣BARD1的协调蛋白稳定性中起着重要作用。我们的工作确定了BRCA1的氨基末端环结构域区域是多泛素化和蛋白酶体介导的蛋白质降解所必需和充分的降解序列。有趣的是，破坏BRCA1泛素E3连接酶活性的RING结构域突变并不影响其自身在卵巢颗粒细胞中的泛素化或降解。蛋白酶体介导的BRCA1和BARD1的降解也发生在camp依赖性的类固醇生成过程中。因此，卵巢颗粒细胞中BRCA1/BARD1蛋白稳定性的动态变化为研究该蛋白复合物在生理条件下的调控提供了一个很好的范例。
Germ-line mutations in BRCA1 predispose women to early-onset, familial breast and ovarian cancers. However, BRCA1 expression is not restricted to breast and ovarian epithelial cells. For example, ovarian BRCA1 expression is enriched in ovarian granulosa cells, which are responsible for ovarian estrogen production in premenopausal women. Furthermore, recent tissue culture and animal studies suggest a functional role of BRCA1 in ovarian granulosa cells. Although levels of BRCA1 are known to fluctuate significantly during folliculogenesis and steroidogenesis, the mechanism by which BRCA1 expression is regulated in granulosa cells remains to be elucidated. Here we show that the ubiquitin-proteasome degradation pathway plays a significant role in the coordinated protein stability of BRCA1 and its partner BARD1 in ovarian granulosa cells. Our work identifies the amino-terminal RING domain-containing region of BRCA1 as the degron sequence that is both necessary and sufficient for polyubiquitination and proteasome-mediated protein degradation. Interestingly, mutations in the RING domain that abolish the ubiquitin E3 ligase activity of BRCA1 do not affect its own ubiquitination or degradation in ovarian granulosa cells. The proteasome-mediated degradation of BRCA1 and BARD1 also occurs during the cAMP-dependent steroidogenic process. Thus, the dynamic changes of BRCA1/BARD1 protein stability in ovarian granulosa cells provide an excellent paradigm for investigating the regulation of this protein complex under physiological conditions.