A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets
A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets
复制标题
DOI：
10.1074/jbc.m212770200
复制
发表时间：
2003-08-08
影响因子：
4.8
通讯作者：
Simon, MC
中科院分区：
文献类型：
--
作者：
Arsham, AM;Howell, JJ;Simon, MC
缺氧触发蛋白质合成的可逆抑制，被认为是重要的能量守恒在O-2-缺乏的环境。哺乳动物雷帕霉素靶蛋白（mTOR）通路整合了多种环境信号以调节翻译以响应营养供应和压力，表明其为O-2调节的候选者。我们在这里表明，缺氧快速和可逆地触发低磷酸化的mTOR及其效应器4 E-BP 1，p70（S6 K），rpS 6，和真核起始因子4G。这些翻译控制蛋白的低氧调节对于通过多种不同的信号传导途径如胰岛素、氨基酸、佛波醇酯和血清的激活是主导性的，并且不依赖于Akt/蛋白激酶B和AMP活化的蛋白激酶磷酸化、ATP水平、ATP：ADP比率和低氧诱导因子-1（HIF-1）。最后，缺氧似乎以类似于雷帕霉素的方式抑制翻译控制蛋白的磷酸化，并且独立于磷酸酶2A（PP 2A）活性。这些数据证明了mTOR途径的一种新的调节模式，并将该途径定位为O-2对细胞代谢和能量学的有力控制点。
Hypoxia triggers a reversible inhibition of protein synthesis thought to be important for energy conservation in O-2-deficient environments. The mammalian target of rapamycin (mTOR) pathway integrates multiple environmental cues to regulate translation in response to nutrient availability and stress, suggesting it as a candidate for O-2 regulation. We show here that hypoxia rapidly and reversibly triggers hypophosphorylation of mTOR and its effectors 4E-BP1, p70(S6K), rpS6, and eukaryotic initiation factor 4G. Hypoxic regulation of these translational control proteins is dominant to activation via multiple distinct signaling pathways such as insulin, amino acids, phorbol esters, and serum and is independent of Akt/protein kinase B and AMP-activated protein kinase phosphorylation, ATP levels, ATP:ADP ratios, and hypoxia-inducible factor-1 (HIF-1). Finally, hypoxia appears to repress phosphorylation of translational control proteins in a manner analogous to rapamycin and independent of phosphatase 2A (PP2A) activity. These data demonstrate a new mode of regulation of the mTOR pathway and position this pathway as a powerful point of control by O-2 of cellular metabolism and energetics.