Differential regulation of estrogen receptor α turnover and transactivation by Mdm2 and stress-inducing agents
Differential regulation of estrogen receptor α turnover and transactivation by Mdm2 and stress-inducing agents
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DOI：
10.1158/0008-5472.can-07-0967
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发表时间：
2007-06-01
期刊：
影响因子：
11.2
通讯作者：
Cavailles, Vincent
中科院分区：
文献类型：
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作者：
Duong, Vanessa;Boulle, Nathalie;Cavailles, Vincent
在哺乳动物细胞中，雌激素处理后雌激素受体α（ERα）的水平会迅速降低，这种调节涉及蛋白酶体降解。我们通过不同的方法表明，致癌的Mdm2泛素连接酶在与p53形成的三元复合物中直接与ERα相互作用，并参与ERα周转的调节（在有或无雌激素的情况下均如此）。多条证据表明，Mdm2的这种作用需要其泛素连接酶活性，并涉及泛素/蛋白酶体途径。此外，在MCF - 7人乳腺癌细胞中，各种p53诱导剂（如紫外线照射）或用RITA（其抑制p53与Mdm2的相互作用）处理可使ERα稳定，并消除其17β - 雌二醇依赖性周转。有趣的是，我们的数据表明，有效的反式激活并不需要配体依赖性受体周转。总之，我们的结果表明，Mdm2癌蛋白和应激诱导剂复杂且有差异地调节人癌细胞中ERα的稳定性和转录活性。
In mammalian cells, the level of estrogen receptor alpha (ER alpha) is rapidly decreased upon estrogen treatment, and this regulation involves proteasome degradation. Using different approaches, we showed that the Mdm2 oncogenic ubiquitin-ligase directly interacts with ER alpha in a ternary complex with p53 and is involved in the regulation of ER alpha turnover (both in the absence or presence of estrogens). Several lines of evidence indicated that this effect of Mdm2 required its ubiquitin-ligase activity and involved the ubiquitin/proteasome pathway. Moreover, in MCF-7 human breast cancer cells, various p53-inducing agents (such as UV irradiation) or treatment with RITA (which inhibits the interaction of p53 with Mdm2) stabilized ER alpha and abolished its 17 beta-estradiol-dependent turnover. Interestingly, our data indicated that ligand-dependent receptor turnover was not required for efficient transactivation. Altogether, our results indicate that the Mdm2 oncoprotein and stress-inducing agents complexly and differentially regulate ER alpha stability and transcriptional activity in human cancer cells.