DeYoung Maurice Phillip, Horak Peter, Sofer Avi, Sgroi Dennis, Ellisen Leif W
Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA.
Genes Dev. 2008 Jan 15;22(2):239-51. doi: 10.1101/gad.1617608.
Hypoxia induces rapid and dramatic changes in cellular metabolism, in part through inhibition of target of rapamycin (TOR) kinase complex 1 (TORC1) activity. Genetic studies have shown the tuberous sclerosis tumor suppressors TSC1/2 and the REDD1 protein to be essential for hypoxia regulation of TORC1 activity in Drosophila and in mammalian cells. The molecular mechanism and physiologic significance of this effect of hypoxia remain unknown. Here, we demonstrate that hypoxia and REDD1 suppress mammalian TORC1 (mTORC1) activity by releasing TSC2 from its growth factor-induced association with inhibitory 14-3-3 proteins. Endogenous REDD1 is required for both dissociation of endogenous TSC2/14-3-3 and inhibition of mTORC1 in response to hypoxia. REDD1 mutants that fail to bind 14-3-3 are defective in eliciting TSC2/14-3-3 dissociation and mTORC1 inhibition, while TSC2 mutants that do not bind 14-3-3 are inactive in hypoxia signaling to mTORC1. In vitro, loss of REDD1 signaling promotes proliferation and anchorage-independent growth under hypoxia through mTORC1 dysregulation. In vivo, REDD1 loss elicits tumorigenesis in a mouse model, and down-regulation of REDD1 is observed in a subset of human cancers. Together, these findings define a molecular mechanism of signal integration by TSC1/2 that provides insight into the ability of REDD1 to function in a hypoxia-dependent tumor suppressor pathway.
缺氧会诱导细胞代谢迅速发生显著变化，部分是通过抑制雷帕霉素靶蛋白（TOR）激酶复合物1（TORC1）的活性来实现的。遗传学研究表明，结节性硬化症肿瘤抑制因子TSC1/2和REDD1蛋白对于果蝇和哺乳动物细胞中TORC1活性的缺氧调节至关重要。缺氧这种作用的分子机制和生理意义仍不清楚。在此，我们证明缺氧和REDD1通过使TSC2从其与抑制性14-3-3蛋白的生长因子诱导的结合中释放出来，从而抑制哺乳动物TORC1（mTORC1）的活性。内源性REDD1对于内源性TSC2/14-3-3的解离以及对缺氧反应时mTORC1的抑制都是必需的。无法结合14-3-3的REDD1突变体在引发TSC2/14-3-3解离和mTORC1抑制方面存在缺陷，而不结合14-3-3的TSC2突变体在向mTORC1传递缺氧信号方面无活性。在体外，REDD1信号缺失通过mTORC1失调促进缺氧条件下的细胞增殖和不依赖贴壁的生长。在体内，REDD1缺失在小鼠模型中引发肿瘤发生，并且在一部分人类癌症中观察到REDD1的下调。总之，这些发现定义了TSC1/2信号整合的分子机制，为REDD1在缺氧依赖性肿瘤抑制途径中发挥作用的能力提供了深入了解。
