Center for Childhood Cancer, Nationwide Children's Hospital, Columbus, OH 43205, USA.
Mol Cell. 2010 Nov 24;40(4):509-20. doi: 10.1016/j.molcel.2010.10.030.
The mTOR complex-1 (mTORC1) coordinates cell growth and metabolism, acting as a restriction point under stress conditions such as low oxygen tension (hypoxia). Hypoxia suppresses mTORC1 signaling. However, the signals by which hypoxia suppresses mTORC1 are only partially understood, and a direct link between hypoxia-driven physiological stress and the regulation of mTORC1 signaling is unknown. Here we show that hypoxia results in ataxia telangiectasia mutated (ATM)-dependent phosphorylation of hypoxia-inducible factor 1-alpha (HIF-1α) on serine(696) and mediates downregulation of mTORC1 signaling. Deregulation of these pathways in pediatric solid tumor xenografts suggests a link between mTORC1 dysregulation and solid tumor development and points to an important role for hypoxic regulation of mTORC1 activity in tumor development.
雷帕霉素靶蛋白复合物 1（mTORC1）协调细胞生长和代谢，在低氧张力（缺氧）等应激条件下充当限制点。缺氧抑制 mTORC1 信号。然而，缺氧抑制 mTORC1 的信号仅部分被理解，并且缺氧驱动的生理应激与 mTORC1 信号调节之间的直接联系尚不清楚。在这里，我们表明缺氧导致共济失调毛细血管扩张突变（ATM）依赖性缺氧诱导因子 1-α（HIF-1α）丝氨酸（696）上的磷酸化，并介导 mTORC1 信号的下调。儿科实体瘤异种移植中这些途径的失调表明 mTORC1 失调与实体瘤发展之间存在联系，并指出缺氧调节 mTORC1 活性在肿瘤发展中的重要作用。
