Mutual Regulation of Hypoxia-Inducible Factor and Mammalian Target of Rapamycin as a Function of Oxygen Availability
Mutual Regulation of Hypoxia-Inducible Factor and Mammalian Target of Rapamycin as a Function of Oxygen Availability
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DOI：
10.1158/1541-7786.mcr-08-0288
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发表时间：
2009-01-01
影响因子：
5.2
通讯作者：
Wiesener, Michael S.
中科院分区：
文献类型：
--
作者：
Knaup, Karl X.;Jozefowski, Katrin;Wiesener, Michael S.
哺乳动物雷帕霉素靶蛋白（mTOR）主要通过控制细胞翻译来调节细胞生长和增殖。大多数肿瘤显示mTOR通路的组成性激活。在缺氧中，mTOR失活，这被认为是细胞维持能量稳态的程序的一部分。然而，某些蛋白质被认为在缺氧期间通过5'末端寡嘧啶道机制优先翻译，关于mTOR依赖性核糖体蛋白S6（rpS 6）的参与存在争议。低氧诱导转录因子（HIF）是低氧适应的主要调节因子，其本身与肿瘤生长密切相关。HIF受mTOR的调控。目前对mTOR对HIF的调控特征和分子氧本身参与的调控还知之甚少。mTOR抑制导致所研究的大多数原代细胞和癌细胞中HIF α蛋白的显著减弱。在严重缺氧下，未观察到mTOR抑制剂的影响;因此，mTOR对HIF α的刺激可能仅在轻度缺氧或甚至常氧下相关。HIF表达和磷酸化rpS 6在实验性肿瘤中呈负相关。在细胞培养中，长时间缺氧废除rpS 6磷酸化，这似乎是部分独立的上游p70 S6激酶。我们发现，缺氧抑制rpS 6在很大程度上依赖于HIF，暗示负反馈回路，这可能会影响细胞的翻译速率和代谢稳态。这些数据表明，低氧微环境使肿瘤细胞对mTOR抑制具有抗性，至少涉及低氧基因活化，这将增加低氧癌症组织中其他已建立的治疗策略的困难。(Mol Cancer Res 2009;7（1）：88-98）
The mammalian target of rapamycin (mTOR) regulates cellular growth and proliferation, mainly by controlling cellular translation. Most tumors show constitutive activation of the mTOR pathway. In hypoxia, mTOR is inactivated, which is believed to be part of the program of the cell to maintain energy homeostasis. However, certain proteins are believed to be preferentially translated during hypoxia via 5' terminal oligopyrimidine tract mechanisms with controversial discussion about the involvement of the mTOR-dependent ribosomal protein S6 (rpS6). The hypoxia-inducible transcription factor (HIF) is the master regulator of hypoxic adaptation and itself strongly implicated in tumor growth. HIF is translationally regulated by mTOR. The regulatory features and the involvement of molecular oxygen itself in this regulation of HIF by mTOR are poorly understood. mTOR inhibition leads to profound attenuation of HIF alpha protein in the majority of primary and cancer cells studied. Under severe hypoxia, no influence of mTOR inhibitors was observed; thus, stimulation of HIF alpha by mTOR may only be relevant under mild hypoxia or even normoxia. HIF expression and phosphorylated rpS6 negatively correlate in experimental tumors. In cell culture, prolonged hypoxia abolishes rpS6 phosphorylation, which seems to be partly independent of the upstream p70S6 kinase. We show that hypoxic repression of rpS6 is largely dependent on HIF, implicating a negative feedback loop, which may influence cellular translational rates and metabolic homeostasis. These data implicate that the hypoxic microenvironment renders tumor cells resistant to mTOR inhibition, at least concerning hypoxic gene activation, which would add to the difficulties of other established therapeutic strategies in hypoxic cancer tissues. (Mol Cancer Res 2009;7(1):88-98)