Transforming growth factor-β1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism
Transforming growth factor-β1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism
复制标题
DOI：
10.1091/mbc.12.1.27
复制
发表时间：
2001-01-01
影响因子：
3.3
通讯作者：
Moses, HL
中科院分区：
文献类型：
--
作者：
Bhowmick, NA;Ghiassi, M;Moses, HL
转化生长因子-β 1（TGF-β）可以抑制肿瘤，但它也可以通过刺激上皮细胞向间充质细胞转分化（EMT）的复杂过程来促进肿瘤进展。调节EMT以响应TGF-β的信号传导途径还不清楚。我们证明收购成纤维细胞样形态，增加N-钙粘蛋白表达，连接E-钙粘蛋白定位的损失，并增加细胞运动性作为TGF-β诱导EMT的标志物。显性负性Smad 3的表达或Smad 7的表达达到阻断生长抑制和对TGF-β的转录应答的水平不会抑制乳腺上皮细胞的间充质分化。相反，我们发现TGF-β在上皮细胞中迅速激活RhoA，并且通过显性负突变体的表达来阻断RhoA或其下游靶点p160（ROCK），抑制TGF-β介导的EMT。这些数据表明，TGF-β快速激活RhoA依赖的信号通路，诱导应力纤维形成和间充质特征。
Transforming growth factor-beta1 (TGF-beta) can be tumor suppressive, but it can also enhance tumor progression by stimulating the complex process of epithelial-to-mesenchymal transdifferentiaion (EMT). The signaling pathway(s) that regulate EMT in response to TGF-beta are not well understood. We demonstrate the acquisition of a fibroblastoid morphology, increased N-cadherin expression, loss of junctional E-cadherin localization, and increased cellular motility as markers for TGF-beta -induced EMT. The expression of a dominant-negative Smad3 or the expression of Smad7 to levels that block growth inhibition and transcriptional responses to TGF-beta do not inhibit mesenchymal differentiation of mammary epithelial cells. In contrast, we show that TGF-beta rapidly activates RhoA in epithelial cells, and that blocking RhoA or its downstream target p160(ROCK), by the expression of dominant-negative mutants, inhibited TGF-beta -mediated EMT. The data suggest that TGF-beta rapidly activates RhoA-dependent signaling pathways to induce stress fiber formation and mesenchymal characteristics.