A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition.
A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition.
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DOI：
10.1038/ncb1905
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发表时间：
2009-08
影响因子：
21.3
通讯作者：
Fuxe, Jonas
中科院分区：
文献类型：
--
作者：
Vincent, Theresa;Neve, Etienne P. A.;Johnson, Jill R.;Kukalev, Alexander;Rojo, Federico;Albanell, Joan;Pietras, Kristian;Virtanen, Ismo;Philipson, Lennart;Leopold, Philip L.;Crystal, Ronald G.;Garcia de Herreros, Antonio;Moustakas, Aristidis;Pettersson, Ralf F.;Fuxe, Jonas
上皮-间充质转化(EMT)是器官发生所必需的，并在肿瘤进展为侵袭性状态时被触发。转化生长因子-β(转化生长因子-β)与RAS、WNT等信号通路协同作用诱导子宫内膜异位转移，但其分子机制尚不清楚。在这里，我们报道了Smad3和Smad4相互作用并与SNAIL1形成复合体，SNAIL1是EMT的转录抑制和启动子。SNAIL1-Smad3/4复合体靶向于紧密连接蛋白CAR和E-钙粘素的基因启动子，在转化生长因子-β诱导的乳腺上皮细胞内胚胎化过程中发挥作用。在转基因细胞中，Snail1和Smad3/4是CAR、occludin、claudin-3和E-cadherin启动子的共同抑制因子。相反，siRNA对SNAIL1和Smad4的共沉默抑制了在EMT过程中CAR和occludin的抑制。此外，Car和E-cadherin的缺失与SNAIL1和Smad3/4在乳腺癌小鼠模型和人类乳腺癌侵袭前沿的核共表达有关。我们认为，SNAIL1-Smad3/4转录复合体的激活代表了EMT过程中基因抑制的一种新机制。
Epithelial-mesenchymal transitions (EMT) are essential for organogenesis and triggered in carcinoma progression into an invasive state. Transforming growth factor-β (TGF-β) cooperates with signalling pathways, such as Ras and Wnt, to induce EMT, but the molecular mechanisms are not clear. Here, we report that SMAD3 and SMAD4 interact and form a complex with SNAIL1, a transcriptional repressor and promoter of EMT. The SNAIL1-SMAD3/4 complex was targeted to the gene promoters of CAR, a tight junction protein, and E-cadherin during TGF-β-driven EMT in breast epithelial cells. SNAIL1 and SMAD3/4 acted as co-repressors of CAR, occludin, claudin-3 and E-cadherin promoters in transfected cells. Conversely, co-silencing of SNAIL1 and SMAD4 by siRNA inhibited the repression of CAR and occludin during EMT. Moreover, loss of CAR and E-cadherin correlated with nuclear co-expression of SNAIL1 and SMAD3/4 in a mouse model of breast carcinoma and at the invasive fronts of human breast cancer. We propose that activation of a SNAIL1-SMAD3/4 transcriptional complex represents a novel mechanism of gene repression during EMT.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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de Herreros, AG
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