CUE domain containing 2 regulates degradation of progesterone receptor by ubiquitin-proteasome
CUE domain containing 2 regulates degradation of progesterone receptor by ubiquitin-proteasome
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DOI：
10.1038/sj.emboj.7601602
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发表时间：
2007-04-04
期刊：
影响因子：
11.4
通讯作者：
Zhang, Xue-Min
中科院分区：
文献类型：
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作者：
Zhang, Pei-Jing;Zhao, Jie;Zhang, Xue-Min
越来越多的证据表明孕激素受体（PR）参与乳腺癌细胞的增殖，并与乳腺癌的发展有关。在本文中，酵母双杂交筛选PR导致CUE域包含2（CUEDC 2），其功能是未知的鉴定。我们的研究结果表明，CUEDC 2与PR相互作用，并通过泛素蛋白酶体途径促进孕酮诱导的PR降解。通过siRNA抑制内源性CUEDC 2几乎消除了孕酮诱导的PR降解，表明CUEDC 2参与了孕酮诱导的PR泛素化和降解。此外，我们确定SUMO化位点赖氨酸-388的PR作为目标的CUEDC 2促进泛素化。CUEDC 2降低PRB的SUMO化，同时促进PRB的Lys-388的泛素化。我们还发现，CUEDC 2抑制PR反式激活，抑制PR刺激快速MAPK活性的能力，并削弱孕酮对乳腺癌细胞生长的影响。因此，我们的研究结果确定了控制PR蛋白水平的关键翻译后机制，并首次为CUEDC 2在乳腺癌增殖中的功能提供了重要的见解。
Accumulated evidence indicates that progesterone receptors (PR) are involved in proliferation of breast cancer cells and are implicated in the development of breast cancer. In this paper, a yeast two-hybrid screen for PR led to the identification of CUE domain containing 2 (CUEDC2), whose function is unknown. Our results demonstrate that CUEDC2 interacts with PR and promotes progesterone-induced PR degradation by the ubiquitin proteasome pathway. The inhibition of endogenous CUEDC2 by siRNA nearly abrogated the progesterone-induced degradation of PR, suggesting that CUEDC2 is involved in progesterone-induced PR ubiquitination and degradation. Moreover, we identify the sumoylation site Lys-388 of PR as the target of CUEDC2-promoted ubiquitination. CUEDC2 decreases the sumoylation while promoting ubiquitination on Lys-388 of PRB. We also show that CUEDC2 represses PR transactivation, inhibits the ability of PR to stimulate rapid MAPK activity, and impairs the effect of progesterone on breast cancer cell growth. Therefore, our results identify a key post-translational mechanism that controls PR protein levels and for the first time provide an important insight into the function of CUEDC2 in breast cancer proliferation.