Cells need to balance metabolic processes, such as protein synthesis, with cellular stresses, such as conditions of low oxygen. The complex mammalian target of rapamycin 1 (mTORC1) is central to the coordination of protein synthesis, and its activity is inhibited during periods of nutrient or oxygen deprivation. Hypoxia acts through REDD1, which inhibits mTORC1. Cam et al. show that cells deficient for the kinase ataxia telangiectasia mutated (ATM) fail to inhibit phosphorylation of mTORC1 targets, exhibit reduced stabilization and nuclear translocation of the transcription factor hypoxia-inducible factor 1α (HIF-1α), and fail to increase the transcription and abundance of REDD1 in response to hypoxia. The activity of ATM isolated from cells exposed to hypoxic conditions toward recombinant HIF-1α was increased compared with cells not exposed to low oxygen, and mass spectrometry analysis identified Ser696 as the site of phosphorylation both in HIF-1α from the in vitro kinase assays and in HIF-1α isolated from cells exposed to hypoxia. Cells expressing only HIF-1α with mutations at this site failed to inhibit mTORC1 signaling in response to hypoxia. Activation of ATM in response to hypoxia occurred in the absence of DNA damage, which is known to induce ATM activity, suggesting an alternative mechanism of activation. ATM-deficient cells were more susceptible to cell death in response to hypoxia, and inhibition of mTOR with rapamycin, inhibition of p53, or expression of HIF-1α promoted cell survival. Xenografts from pediatric solid tumors (with hypoxic regions) showed reduced abundance of ATM and increased phosphorylation of an mTORC1 target compared with acute lymphocytic leukemia xenografts (nonhypoxic) or the tissues of origin of the solid tumors. These results suggest that ATM is necessary for inhibition of mTORC1 activity during periods of hypoxia and that solid tumor growth may involve increased mTORC1 signaling as a consequence of reduced ATM activity.
H. Cam, J. B. Easton, A. High, P. J. Houghton, mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α. Mol. Cell 40, 509–520 (2010). [Online Journal]