Cross-talk between transforming growth factor-β and estrogen receptor signaling through Smad3
Cross-talk between transforming growth factor-β and estrogen receptor signaling through Smad3
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DOI：
10.1074/jbc.m105316200
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发表时间：
2001-11-16
影响因子：
4.8
通讯作者：
Saatcioglu, F
中科院分区：
文献类型：
--
作者：
Matsuda, T;Yamamoto, T;Saatcioglu, F
转化生长因子-β（TGF-β）在创伤愈合和组织修复期间的胚胎发育、器官发生和生理性结缔组织重塑以及在致癌作用中起中心作用。雌激素在多种生物学事件中起关键作用，如女性生殖器官的发育和维持以及骨和脂质代谢。以前的研究表明，雌激素抑制TGF-β诱导的基因表达，如肾系膜细胞中的IV型胶原。然而，介导这种拮抗作用的分子机制是未知的。为了阐明TGF-β和雌激素受体（ER）信号通路之间的相互作用机制，我们在人肾癌细胞中重建了TGF-β和ER信号通路。在这里，我们证明了TGF-β诱导的Sma和MAD相关蛋白3（Smad 3）活性的激活，TGF-β信号传导的主要细胞内转导子之一，被ER抑制，而ER介导的转录激活被TGF-β信号传导增强。我们提供的证据表明，雌激素和TGF-β信号通路之间的这种双向串扰是Smad 3和ER之间直接物理相互作用的结果。这些发现对多种疾病状态有意义，如肾功能、动脉粥样硬化和乳腺癌的病理生理学。
Transforming growth factor-beta (TGF-beta) plays central roles in embryonic development, organogenesis, and physiologic connective tissue remodeling during wound healing and tissue repair as well as in carcinogenesis. Estrogens have key roles in a variety of biological events, such as the development and maintenance of female reproductive organs and bone and lipid metabolism. Previous studies demonstrated that estrogens suppress TGF-beta -induced gene expression, such as type IV collagen in kidney mesangial cells. However, the molecular mechanisms that mediate this antagonistic effect are unknown. To elucidate the mechanisms of cross-talk between TGF-beta and estrogen receptor (ER) signaling pathways, we reconstituted TGF-beta and ER signaling in human kidney carcinoma cells. Here we demonstrate that TGF-beta -induced activation of Sma and MAD-related protein 3 (Smad3) activity, one of the major intracellular transducers of TGF-beta signaling, was suppressed by ER, whereas ER-mediated transcriptional activation was enhanced by TGF-beta signaling. We provide evidence that this two-way cross-talk between the estrogen and TGF-beta signaling pathways was the result of direct physical interactions between Smad3 and ER. These findings have implications for a variety of disease states, such as the pathophysiology of kidney function, atherosclerosis, and breast cancer.