Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex
Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex
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DOI：
10.1101/gad.1256804
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发表时间：
2004-12-01
影响因子：
10.5
通讯作者：
Kaelin, WG
中科院分区：
文献类型：
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作者：
Brugarolas, J;Lei, K;Kaelin, WG
哺乳动物雷帕霉素靶标(MTOR)是蛋白质合成的中枢调节因子，其活性受多种信号调节。能量耗竭和低氧导致mTOR抑制。虽然能量耗竭通过LKB1激活AMP激活的蛋白激酶(AMPK)和随后的TSC2磷酸化来抑制mTOR，但缺氧抑制mTOR的机制尚不清楚。在这里，我们证明了低氧抑制mTOR需要TSC1/TSC2肿瘤抑制复合体和低氧诱导基因Redd1/RTP801。通过丢失TSC1或TSC2而破坏TSC1/TSC2复合体可以阻断缺氧对mTOR的影响，这是通过mTOR靶标S6K和4E-BP1的变化来衡量的，并导致缺氧诱导因子(HIF)的异常积聚。与能量消耗相反，低氧抑制mTOR不需要AMPK或LKB1。低氧下调mTOR活性需要从头合成mRNA，并与低氧诱导的Redd1基因表达增加相关。阻断Redd1可以消除缺氧对mTOR的抑制，并且Redd1的过表达足以以TSC1/TSC2依赖的方式下调S6K的磷酸化。低氧抑制mTOR功能可能对肿瘤抑制很重要，因为TSC2缺陷细胞在低氧条件下维持异常高的细胞增殖水平。
Mammalian target of rapamycin (mTOR) is a central regulator of protein synthesis whose activity is modulated by a variety of signals. Energy depletion and hypoxia result in mTOR inhibition. While energy depletion inhibits mTOR through a process involving the activation of AMP-activated protein kinase (AMPK) by LKB1 and subsequent phosphorylation of TSC2, the mechanism of mTOR inhibition by hypoxia is not known. Here we show that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the hypoxia-inducible gene REDD1/RTP801. Disruption of the TSC1/TSC2 complex through loss of TSC1 or TSC2 blocks the effects of hypoxia on mTOR, as measured by changes in the mTOR targets S6K and 4E-BP1, and results in abnormal accumulation of Hypoxia-inducible factor (HIF). In contrast to energy depletion, mTOR inhibition by hypoxia does not require AMPK or LKB1. Down-regulation of mTOR activity by hypoxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxia-inducible REDD1 gene. Disruption of REDD1 abrogates the hypoxia-induced inhibition of mTOR, and REDD1 overexpression is sufficient to down-regulate S6K phosphorylation in a TSC1/TSC2-dependent manner. Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia.