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首页> 外文期刊>Journal of Cellular Physiology >p62 Promotes Amino Acid Sensitivity of mTOR Pathway and Hepatic Differentiation in Adult Liver Stem/Progenitor Cells
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p62 Promotes Amino Acid Sensitivity of mTOR Pathway and Hepatic Differentiation in Adult Liver Stem/Progenitor Cells

机译：p62促进氨基酸mTOR的敏感性途径和成人肝分化肝干细胞/祖细胞

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Autophagy is a homeostatic process regulating turnover of impaired proteins and organelles, and p62 (sequestosome-1, SQSTM1) functions as the autophagic receptor in this process. p62 also functions as a hub for intracellular signaling such as that in the mammalian target of rapamycin (mTOR) pathway. Liver stem/progenitor cells have the potential to differentiate to form hepatocytes or cholangiocytes. In this study, we examined effects of autophagy, p62, and associated signaling on hepatic differentiation. Adult stem/progenitor cells were isolated from the liver of mice with chemically induced liver injury. Effects of autophagy, p62, and related signaling pathways on hepatic differentiation were investigated by silencing the genes for autophagy protein 5 (ATG5) and/or SQSTM1/p62 using small interfering RNAs. Hepatic differentiation was assessed based on increased albumin and hepatocyte nuclear factor 4, as hepatocyte markers, and decreased cytokeratin 19 and SOX9, as stem/progenitor cell markers. These markers were measured using quantitative RT-PCR, immunofluorescence, and Western blotting. ATG5 silencing decreased active LC3 and increased p62, indicating inhibition of autophagy. Inhibition of autophagy promoted hepatic differentiation in the stem/progenitor cells. Conversely, SQSTM1/p62 silencing impaired hepatic differentiation. A suggested mechanism for p62-dependent hepatic differentiation in our study was activation of the mTOR pathway by amino acids. Amino acid activation of mTOR signaling was enhanced by ATG5 silencing and suppressed by SQSTM1/p62 silencing. Our findings indicated that promoting amino acid sensitivity of the mTOR pathway is dependent on p62 accumulated by inhibition of autophagy and that this process plays an important role in the hepatic differentiation of stem/progenitor cells. J. Cell. Physiol. 232: 2112-2124, 2017. (c) 2016 Wiley Periodicals, Inc.
机译：自噬是一个稳态的过程管理受损的蛋白质和细胞器的营业额,p62 (sequestosome-1 SQSTM1)功能在这一过程中自噬受体。函数作为细胞内信号的中心例如,在哺乳动物雷帕霉素靶(mTOR)通路。分化形成的潜力肝细胞或cholangiocytes。研究自噬的影响、p62和在肝分化相关的信号。成人干细胞/祖细胞被隔绝小鼠的肝脏与化学诱导肝脏受伤。信号通路在肝分化研究基因沉默自噬蛋白5 (ATG5)和/或SQSTM1 / p62使用小干扰rna。分化是评估的基础上增加了白蛋白和肝细胞的核因子4肝细胞标记,和减少细胞角蛋白19SOX9,干细胞/祖细胞标记。使用定量rt - pcr标记测量,免疫荧光和免疫印迹。沉默LC3和增加p62减少活跃,表明抑制自噬。自噬促进肝中分化干细胞/祖细胞。沉默受损肝细胞分化。建议p62-dependent肝的机制分化在我们的研究中被激活由氨基酸mTOR通路。激活mTOR信号被ATG5增强沉默和抑制SQSTM1 / p62沉默。我们的研究结果表明,促进氨基酸敏感性mTOR的路径依赖p62抑制自噬和积累起来的这个过程中发挥着重要作用肝干细胞/祖细胞的分化。j .细胞。威利期刊公司。

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