Smad4 as a transcription corepressor for estrogen receptor α
Smad4 as a transcription corepressor for estrogen receptor α
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DOI：
10.1074/jbc.m212332200
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发表时间：
2003-04-25
影响因子：
4.8
通讯作者：
Cao, X
中科院分区：
文献类型：
--
作者：
Wu, LY;Wu, YL;Cao, X
抗雌激素化合物在不同的组织中表现出多种不同的作用，被广泛用于治疗骨质疏松症、乳腺癌和其他疾病。通过对分子机制的研究，我们发现Smad4是骨形态发生蛋白(BMP)/转化生长因子- β (tgf - β)信号通路中常见的信号传感器，可作为人雌激素受体α (er - α)的转录辅助抑制因子。内源性erα与Smad4共免疫沉淀，其相互作用是由抗雌激素配体如他莫昔芬、雷洛昔芬和德洛昔芬诱导的，这在染色质免疫沉淀实验中得到证实。当erα与雌激素靶基因启动子内的雌激素反应元件结合时，Smad4和erα形成复合物。重要的是，Smad4的表达抑制乳腺癌细胞中抗雌激素诱导的荧光素酶活性和雌激素下游靶基因转录。相互作用结构域的映射表明，ERalpha的激活功能1 （AF1）结构域是其与Smad4相互作用的必要条件，而MH1结构域和Smad4的连接子区域是相互作用的必要条件。我们的发现代表了一种新的机制，即tgf - β可能通过smad4介导的与雌激素的串扰来调节细胞命运。
Antiestrogen compounds exhibit a variety of different effects in different tissues and are widely used for the treatment of osteoporosis, breast cancer, and other diseases. Upon examining the molecular mechanisms, we found that Smad4, a common signal transducer in the bone morphogenetic protein (BMP)/transforming growth factor-beta (TGF-beta) signaling pathway, functions as a transcription corepressor for human estrogen receptor alpha (ERalpha). Endogenous ERalpha was co-immunoprecipitated with Smad4, and the interaction was induced by antiestrogen ligands such as tamoxifen, raloxifene, and droloxifen, which was confirmed in chromatin immunoprecipitation assays. Smad4 and ERalpha form a complex when ERalpha binds to the estrogen-responsive element within the estrogen target gene promoter. Importantly, the expression of Smad4 inhibits both antiestrogen-induced luciferase activity and estrogen downstream target gene transcription in breast cancer cells. Mapping of the interaction domains indicates that the activation function 1 (AF1) domain of ERalpha is essential for its interaction with Smad4, while the MH1 domain and linker region of Smad4 are essential for the interaction. Our findings represent a novel mechanism that TGF-beta may regulate cell fate through Smad4-mediated crosstalk with estrogen.