Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition.
Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition.
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发表时间：
2004
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通讯作者：
J. Zavadil;L. Cermak;Noemí Soto-Nieves;E. Böttinger
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作者：
J. Zavadil;L. Cermak;Noemí Soto-Nieves;E. Böttinger
上皮细胞向间充质细胞转化（EMT）是胚胎发育所需的细胞可塑性的基础，在晚期癌发生中经常观察到。转化生长因子-β（TGF-β）在体外诱导上皮细胞中的EMT表型，并与体内EMT相关。在这里，我们报告了乳腺、肾小管和表皮上皮细胞EMT开始时，TGF-β诱导了毛状/分裂增强子相关转录抑制子Hey 1和Notch配体Jagged 1（Jag 1）的表达。HEY 1的表达谱是双相的，包括立即早期的Smad 3依赖的，Jagged 1/Notch独立的激活，随后是延迟的，间接的Jagged 1/Notch依赖的激活。TGF-β诱导的EMT被HEY 1或JAG 1的RNA沉默以及Notch的化学失活所阻断。EMT表型，双相激活的Hey 1，和延迟表达的Jag 1诱导TGF-β在野生型，但不是在Smad 3缺陷，原代小鼠肾小管上皮细胞。我们的研究结果确定了一个新的机制，功能整合的锯齿状蛋白1/Notch信号和协调激活的Hey 1转录抑制因子控制的TGF-β/Smad 3，并证明Smad 3，Hey 1，和锯齿状蛋白1/Notch介导的TGF-β诱导的EMT的功能作用。
Epithelial-to-mesenchymal transitions (EMTs) underlie cell plasticity required in embryonic development and frequently observed in advanced carcinogenesis. Transforming growth factor-beta (TGF-beta) induces EMT phenotypes in epithelial cells in vitro and has been associated with EMT in vivo. Here we report that expression of the hairy/enhancer-of-split-related transcriptional repressor Hey1, and the Notch-ligand Jagged1 (Jag1), was induced by TGF-beta at the onset of EMT in epithelial cells from mammary gland, kidney tubules, and epidermis. The HEY1 expression profile was biphasic, consisting of immediate-early Smad3-dependent, Jagged1/Notch-independent activation, followed by delayed, indirect Jagged1/Notch-dependent activation. TGF-beta-induced EMT was blocked by RNA silencing of HEY1 or JAG1, and by chemical inactivation of Notch. The EMT phenotype, biphasic activation of Hey1, and delayed expression of Jag1 were induced by TGF-beta in wild-type, but not in Smad3-deficient, primary mouse kidney tubular epithelial cells. Our findings identify a new mechanism for functional integration of Jagged1/Notch signalling and coordinated activation of the Hey1 transcriptional repressor controlled by TGF-beta/Smad3, and demonstrate functional roles for Smad3, Hey1, and Jagged1/Notch in mediating TGF-beta-induced EMT.