缺氧诱导的能量应激调节mRNA翻译和细胞生长。
Hypoxia-induced energy stress regulates mRNA translation and cell growth.
作者信息
Liu Liping, Cash Timothy P, Jones Russell G, Keith Brian, Thompson Craig B, Simon M Celeste
机构信息
Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
出版信息
Mol Cell. 2006 Feb 17;21(4):521-31. doi: 10.1016/j.molcel.2006.01.010.
Oxygen (O2) deprivation, or hypoxia, has profound effects on cell metabolism and growth. Cells can adapt to low O2 in part through activation of hypoxia-inducible factor (HIF). We report here that hypoxia inhibits mRNA translation by suppressing multiple key regulators, including eIF2alpha, eEF2, and the mammalian target of rapamycin (mTOR) effectors 4EBP1, p70S6K, and rpS6, independent of HIF. Hypoxia results in energy starvation and activation of the AMPK/TSC2/Rheb/mTOR pathway. Hypoxic AMP-activated protein kinase (AMPK) activation also leads to eEF2 inhibition. Moreover, hypoxic effects on cellular bioenergetics and mTOR inhibition increase over time. Mutation of the TSC2 tumor suppressor gene confers a growth advantage to cells by repressing hypoxic mTOR inhibition and hypoxia-induced G1 arrest. Together, eIF2alpha, eEF2, and mTOR inhibition represent important HIF-independent mechanisms of energy conservation that promote survival under low O2 conditions.
缺氧，即氧（O2）剥夺，对细胞代谢和生长具有深远影响。细胞可部分通过缺氧诱导因子（HIF）的激活来适应低氧环境。我们在此报告，缺氧通过抑制包括真核生物翻译起始因子2α（eIF2α）、真核生物延伸因子2（eEF2）以及雷帕霉素靶蛋白（mTOR）效应分子4EBP1、p70S6K和核糖体蛋白S6（rpS6）在内的多个关键调节因子，独立于HIF抑制mRNA翻译。缺氧导致能量饥饿并激活AMPK/TSC2/Rheb/mTOR信号通路。缺氧激活的AMP激活蛋白激酶（AMPK）也会导致eEF2受到抑制。此外，缺氧对细胞生物能量学和mTOR的抑制作用会随着时间的推移而增强。TSC2肿瘤抑制基因的突变通过抑制缺氧诱导的mTOR抑制和缺氧诱导的G1期阻滞，赋予细胞生长优势。总之，eIF2α、eEF2和mTOR的抑制代表了在低氧条件下促进细胞存活的重要的不依赖HIF的能量节约机制。
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