YAP modulates TGF-β1-induced simultaneous apoptosis and EMT through upregulation of the EGF receptor.
YAP modulates TGF-β1-induced simultaneous apoptosis and EMT through upregulation of the EGF receptor.
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YAP 通过上调 EGF 受体调节 TGF-β1 诱导的同时细胞凋亡和 EMT
DOI：
10.1038/srep45523
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发表时间：
2017-04-20
影响因子：
4.6
通讯作者：
Song J
中科院分区：
文献类型：
--
作者：
Liu Y;He K;Hu Y;Guo X;Wang D;Shi W;Li J;Song J
雅普是一种转录辅助调节因子，在多种病理生理过程中发挥重要作用，包括细胞的存活和死亡。然而，雅普对TGF-β 1同时介导的细胞凋亡和EMT的影响尚不清楚。在这项研究中，我们证明，雅普可以调节细胞命运的凋亡与EMT作为一个生存因子。在小鼠乳腺上皮细胞（NMuMG）中过表达雅普可抑制TGF-β 1诱导的细胞凋亡，使细胞反应主要向EMT方向转变。相反，敲低雅普可诱导自发凋亡，并增强TGF-β 1诱导的凋亡，导致经历EMT的存活细胞比例急剧下降。这些数据表明，雅普是调节细胞对TGF-β 1反应的重要因子。进一步研究表明，雅普可调节EGFR的表达水平和活化。敲低或抑制EGFR可消除雅普对细胞凋亡的抑制作用，而EGF激活EGFR可显著减少敲低雅普引起的细胞凋亡。结果表明，EGFR及其活化是YAP介导的抑制TGF-β 1诱导的细胞凋亡的关键。本研究为TGF-β 1介导的细胞凋亡和EMT的同时发生提供了新的认识。
YAP is a transcriptional co-regulator that plays important roles in various patho-physiological processes, including the survival and death of cells. However, the effect of YAP on apoptosis and EMT, simultaneously mediated by TGF-β1, is not known. In this study, we demonstrate that YAP can modulate cell fate of apoptosis versus EMT by acting as a surviving factor. Overexpression of YAP in mouse mammary epithelial (NMuMG) cells suppressed TGF-β1-induced apoptosis, which shifted the cellular response predominantly toward EMT. In contrast, knockdown of YAP induced spontaneous apoptosis and enhanced TGF-β1-induced apoptosis, leading to a sharp decrease in the proportion of surviving cells that underwent EMT. These data suggest that YAP is an essential factor for modulating cellular responses to TGF-β1. Further investigation showed that YAP could regulate the expression level and activation of EGFR. Knockdown or inhibition of EGFR abolished the suppressive effect of YAP on apoptosis, whereas activation of EGFR by EGF significantly reduced apoptosis caused by the knockdown of YAP. The results indicate that EGFR and its activation are critical for YAP-mediated suppression of TGF-β1-induced apoptosis. This study provides a new understanding of the regulatory mechanism underlying the determination of cell fate in response to TGF-β1-mediated simultaneous apoptosis and EMT.