Zavadil Jiri, Cermak Lukas, Soto-Nieves Noemi, Böttinger Erwin P
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
EMBO J. 2004 Mar 10;23(5):1155-65. doi: 10.1038/sj.emboj.7600069. Epub 2004 Feb 19.
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.
上皮-间质转化（EMT）是胚胎发育过程中细胞可塑性的基础，并且在晚期癌症发生过程中经常被观察到。转化生长因子-β（TGF-β）在体外可诱导上皮细胞出现EMT表型，并且在体内与EMT相关。在此我们报告，在来自乳腺、肾小管和表皮的上皮细胞发生EMT起始阶段，TGF-β可诱导毛状/分裂增强子相关转录抑制因子Hey1以及Notch配体Jagged1（Jag1）的表达。HEY1的表达谱呈双相性，包括早期由Smad3依赖性、Jagged1/Notch非依赖性激活，随后是延迟的、间接的Jagged1/Notch依赖性激活。通过对HEY1或JAG1进行RNA干扰以及对Notch进行化学失活，可阻断TGF-β诱导的EMT。在野生型而非Smad3缺陷型的原代小鼠肾小管上皮细胞中，TGF-β可诱导EMT表型、Hey1的双相激活以及Jag1的延迟表达。我们的研究结果确定了一种新机制，即Jagged1/Notch信号的功能整合以及由TGF-β/Smad3控制的Hey1转录抑制因子的协同激活，并证明了Smad3、Hey1以及Jagged1/Notch在介导TGF-β诱导的EMT中的功能作用。
