Role of Hypoxia-Induced Fibronectin-Integrin β1 Expression in Embryonic Stem Cell Proliferation and Migration: Involvement of PI3K/Akt and FAK
Role of Hypoxia-Induced Fibronectin-Integrin β1 Expression in Embryonic Stem Cell Proliferation and Migration: Involvement of PI3K/Akt and FAK
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DOI：
10.1002/jcp.22358
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发表时间：
2011-02-01
影响因子：
5.6
通讯作者：
Han, Ho Jae
中科院分区：
文献类型：
--
作者：
Lee, Sang Hun;Lee, Yu Jin;Han, Ho Jae
细胞迁移在很大程度上依赖于整合素（IN）与细胞外基质的结合，并且参与这些过程的几种信号传导途径已被证明可被缺氧修饰。因此，本研究的目的是确定缺氧对小鼠胚胎干细胞（mESCs）中纤维连接蛋白（FN）和IN β 1表达的影响及其调节增殖的信号通路。FN和IN β 1表达在缺氧24 h时显著增加。缺氧也增加了细胞附着，这是伴随着FN和IN β 1的结合水平的增加。缺氧诱导的FN表达通过增加的磷脂酰肌醇3激酶（PI 3 K）/Akt和哺乳动物雷帕霉素靶蛋白（mTOR）磷酸化以及缺氧诱导因子-la（HIF-1 α）表达来介导。此外，在缺氧条件下，粘着斑激酶（FAK）和Src磷酸化增加的时间依赖性的方式，这些增加被阻断IN β 1抗体。此外，缺氧诱导的F-actin分布和细胞迁移（基质金属蛋白酶-2和-9的活化）的增加被IN β 1抗体抑制。事实上，缺氧增加了细胞周期调节蛋白和DNA合成的水平。总之，缺氧通过PI 3 K/Akt、mTOR和HIF-1 α途径产生FN-IN β 1，然后激活FAK，从而增加mESC的增殖和迁移。J.细胞。226：484-493，2011。(C)2010 Wiley-Liss，Inc.
Cell migration is largely dependent on integrin (IN) binding to the extracellular matrix, and several signaling pathways involved in these processes have been shown to be modified by hypoxia. Therefore, the aim of this study was to determine the influence of hypoxia on fibronectin (FN) and IN beta 1 expression in mouse embryonic stem cells (mESCs) and their signaling pathways to modulate proliferation. FN and IN beta 1 expression were significantly increased in hypoxic mESCs by 24 h. Hypoxia also increased cell attachment, which was accompanied by concomitant increases in the binding level of FN and IN beta 1. Hypoxia-induced FN expression was mediated by increased phosphatidylinositol 3 kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) phosphorylation, and hypoxia-inducible factor-la (HIF-1 alpha) expression. Moreover, under hypoxic conditions, focal adhesion kinase (FAK) and Src phosphorylation were increased in a time-dependent fashion; these increases were blocked by IN beta 1 antibody. In addition, the hypoxia induced increase of F-actin distribution and cell migration (activation of matrix metalloproteinase-2 and -9) was inhibited by IN beta 1 antibody. Indeed, hypoxia increased the level of cell-cycle regulatory protein and DNA synthesis. In conclusion, hypoxia increases the proliferation and migration of mESCs via FN-IN beta 1 production through the PI3K/Akt, mTOR, and HIF-1 alpha pathways, followed by FAK activation. J. Cell. Physiol. 226: 484-493, 2011. (C) 2010 Wiley-Liss, Inc.