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 serine696 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.
Highlights
► Negative regulation of mTORC1 signaling by hypoxia is ATM dependent ► ATM-dependent phosphorylation of HIF1α(Ser696) is required for mTORC1 regulation ► Maintained mTORC1 signaling in ATM−/− cells under hypoxia leads to apoptosis ► Childhood solid tumors show 10- to 20-fold lower ATM levels than leukemias
