Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Biochem J. 2011 Aug 1;437(3):515-20. doi: 10.1042/BJ20101500.
EndMT (endothelial-mesenchymal transition) is a critical process of cardiac development and disease progression. However, little is know about the signalling mechanisms that cause endothelial cells to transform into mesenchymal cells. In the present paper we show that TGF-β2 (transforming growth factor-β2) stimulates EndMT through the Smad, MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase], PI3K (phosphinositide 3-kinase) and p38 MAPK signalling pathways. Inhibitors of these pathways prevent TGF-β2-induced EndMT. Furthermore, we show that all of these pathways are essential for increasing expression of the cell-adhesion-suppressing transcription factor Snail. Inhibition of Snail with siRNA (small interfering RNA) prevents TGF-β2-induced EndMT. However, overexpression of Snail is not sufficient to cause EndMT. Chemical inhibition of GSK-3β (glycogen synthase kinase-3β) allows EndMT to be induced by Snail overexpression. Expression of a mutant Snail protein that is resistant to GSK-3β-dependent inactivation also promotes EndMT. These results provide the foundation for understanding the roles of specific signalling pathways in mediating EndMT.
EndMT（内皮-间充质转化）是心脏发育和疾病进展的关键过程。然而，对于导致内皮细胞转化为间充质细胞的信号机制知之甚少。在本文中，我们表明 TGF-β2（转化生长因子-β2）通过 Smad、MEK[MAPK（丝裂原激活蛋白激酶）/ERK（细胞外信号调节激酶）激酶]、PI3K（磷酸肌醇 3-激酶）和 p38 MAPK 信号通路刺激 EndMT。这些途径的抑制剂可预防 TGF-β2 诱导的 EndMT。此外，我们表明，所有这些途径对于增加细胞粘附抑制转录因子 Snail 的表达都是必不可少的。用 siRNA（小干扰 RNA）抑制 Snail 可防止 TGF-β2 诱导的 EndMT。然而，Snail 的过表达不足以引起 EndMT。化学抑制 GSK-3β（糖原合酶激酶-3β）可允许 Snail 过表达诱导 EndMT。表达对 GSK-3β 依赖性失活有抗性的突变型 Snail 蛋白也促进 EndMT。这些结果为理解特定信号通路在介导 EndMT 中的作用提供了基础。
