TGF-β1 regulates cell fate during epithelial-mesenchymal transition by upregulating survivin.
TGF-β1 regulates cell fate during epithelial-mesenchymal transition by upregulating survivin.
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DOI：
10.1038/cddis.2013.244
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发表时间：
2013-07-04
影响因子：
9
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转化生长因子β(TGFR-β)超家族成员是一类多功能细胞因子，调节细胞周期停滞、分化、形态发生和细胞凋亡等多种细胞过程。转化生长因子-β促进细胞外基质的产生和形态改变。转化生长因子-β的形态发生反应包括细胞迁移和上皮-间充质转化，它们在胚胎发生、纤维化疾病的发展和晚期癌症的扩散中起关键作用。本研究的目的是阐明转化生长因子-β如何调控视网膜色素上皮细胞的命运。转化生长因子-β-1促进ARPE-19细胞周期进程和视网膜母细胞瘤蛋白(Rb)的磷酸化。转化生长因子-β-1诱导Survivin表达，进而稳定微管蛋白和Aurora B的表达。RT-β和Western印迹分析显示，经转化生长因子-BMP-1作用后，ARPE-19细胞中Survivin表达增加。当Survivin被耗尽时，转化生长因子-β-1诱导细胞周期停滞和细胞凋亡，并降低Rb的磷酸化。综上所述，目前的研究表明，在人RPE细胞中诱导EMT上调Survivin，导致Survivin依赖的细胞周期停滞和凋亡抑制。转化生长因子-β-1对细胞的作用取决于细胞周期状态，转化生长因子-β-1通过Survivin调节细胞周期。
Members of the transforming growth factor beta (TGF-β) superfamily are multifunctional cytokines that regulate several cellular processes, including cell cycle arrest, differentiation, morphogenesis, and apoptosis. TGF-β promotes extracellular matrix production and morphological change. Morphogenetic responses to TGF-β include cell migration and epithelial–mesenchymal transition (EMT), which are critical during embryogenesis, development of fibrotic diseases, and the spreading of advanced carcinomas. The purpose of this study was to clarify how TGF-β regulates the fate of retinal pigment epithelial (RPE) cells. TGF-β1 promoted cell cycle progression and phosphorylation of retinoblastoma protein (Rb) in ARPE-19 cells. TGF-β1 induced survivin expression, which in turn stabilized tubulin and Aurora B. RT-PCR and western blot analysis revealed that survivin expression increased in ARPE-19 cells following TGF-β1 treatment. When survivin was depleted, TGF-β1 induced cell cycle arrest and apoptosis and also reduced Rb phosphorylation. In conclusion, the present study shows that induction of EMT in human RPE cells upregulates survivin, leading to survivin-dependent inhibition of cell cycle arrest and apoptosis. Whether cells undergo EMT or apoptosis in response to TGF-β1 is dependent on their cell cycle state, and TGF-β1 regulates the cell cycle via survivin.