Estrogen Inhibits Transforming Growth Factor β Signaling by Promoting Smad2/3 Degradation
Estrogen Inhibits Transforming Growth Factor β Signaling by Promoting Smad2/3 Degradation
复制标题
DOI：
10.1074/jbc.m109.093039
复制
发表时间：
2010-05-07
影响因子：
4.8
通讯作者：
Yanagisawa, Junn
中科院分区：
文献类型：
--
作者：
Ito, Ichiaki;Hanyu, Aki;Yanagisawa, Junn
雌激素是一种刺激细胞增殖的生长因子。雌激素的作用是通过雌激素受体ER α和ER β介导的，它们作为配体诱导的转录因子发挥作用，属于核受体超家族。另一方面，TGF-β作为细胞生长抑制剂，其信号传导由Smads转导。虽然已经对雌激素/ER α和TGF-β/Smad信号通路之间的相互作用进行了大量的研究，但其分子机制仍有待确定。在这里，我们发现ER α通过降低Smad蛋白水平来抑制TGF-β信号传导。ER α介导的Smad水平降低不需要ER α的DNA结合能力，这意味着ER α通过一种新的非基因组机制对抗TGF-β的作用。我们的分析表明，ER α与Smad和泛素连接酶Smurf形成蛋白复合物，并以雌激素依赖的方式增强Smad泛素化和随后的降解。我们的观察为ER α的非基因组功能的分子机制提供了新的见解
Estrogen is a growth factor that stimulates cell proliferation. The effects of estrogen are mediated through the estrogen receptors, ER alpha and ER beta, which function as ligand-induced transcription factors and belong to the nuclear receptor superfamily. On the other hand, TGF-beta acts as a cell growth inhibitor, and its signaling is transduced by Smads. Although a number of studies have been made on the cross-talk between estrogen/ER alpha and TGF-beta/Smad signaling, whose molecular mechanisms remain to be determined. Here, we show that ER alpha inhibits TGF-beta signaling by decreasing Smad protein levels. ER alpha-mediated reductions in Smad levels did not require the DNA binding ability of ER alpha, implying that ER alpha opposes the effects of TGF-beta via a novel non-genomic mechanism. Our analysis revealed that ER alpha formed a protein complex with Smad and the ubiquitin ligase Smurf, and enhanced Smad ubiquitination and subsequent degradation in an estrogen-dependent manner. Our observations provide new insight into the molecular mechanisms governing the non-genomic functions of ER alpha