Inhibition of hypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic siqnaling: role of P13-K and Akt kinase upon rac1
Inhibition of hypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic siqnaling: role of P13-K and Akt kinase upon rac1
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DOI：
10.1038/sj.cdd.4401172
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发表时间：
2003-05-01
影响因子：
12.4
通讯作者：
Suzuki, S
中科院分区：
文献类型：
--
作者：
Ozaki, M;Haga, S;Suzuki, S
rac1调控的活性氧（ROS）的产生与细胞凋亡有关。相反，多效蛋白激酶At保护细胞免于凋亡。然而，rac1和Akt各自的促凋亡和抗凋亡机制以及这些机制之间的交集尚不完全清楚。在原代肝细胞缺氧/再氧化（H/R）诱导的氧化应激和细胞凋亡模型中，促生存肝细胞生长因子（HGF）激活PI3-K Akt轴可抑制H/R刺激的rac1激活和细胞内ROS生成，并抑制细胞凋亡。抑制PI3-K或Akt活性可消除HGF对rac1活性和rac1调控的氧化应激的抑制作用。此外，在缺乏HGF的情况下，Akt或PI3-K的组成性激活足以磷酸化rac1，抑制rac1的激活，并抑制rac1调控的ROS产生。这些发现表明，生长因子刺激的PI3-K-Akt的激活是通过抑制促凋亡、促氧化的rac1 GTPase的激活来抑制细胞内氧化应激和细胞凋亡的必要和充分条件。
Rac1-regulated reactive oxygen species (ROS) production has been implicated in apoptosis. In contrast, pleiotropic protein kinase At protects against apoptosis. However, the pro- and antiapoptotic mechanisms of rac1 and Akt, respectively, and the intersection between these mechanisms are incompletely understood. In a model of oxidative stress and apoptosis induced by hypoxia/reoxygenation (H/R) in primary hepatocytes, activation of the PI3-K Akt axis by the prosurvival hepatocyte growth factor (HGF) inhibited H/R-stimulated rac1 activation and intracellular ROS production, and suppressed apoptosis. Suppression of PI3-K or Akt activity abrogated the inhibitory effect of HGF on rac1 activity and rac1-regulated oxidative stress. Furthermore, constitutive activation of Akt or PI3-K in the absence of HGF was sufficient to phosphorylate rac1, inhibit rac1 activation, and suppress rac1-regulated ROS production. These findings demonstrate that growth factor-stimulated activation of PI3-K-Akt is necessary and sufficient to suppress intracellular oxidative stress and apoptosis by inhibiting activation of proapoptotic, prooxidative rac1 GTPase.