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Mol Cell. 2010 Nov 24;40(4):509-20. doi: 10.1016/j.molcel.2010.10.030.

mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α.

Author information

1
Center for Childhood Cancer, Nationwide Children's Hospital, Columbus, OH 43205, USA.

Abstract

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.

PMID:
21095582
PMCID:
PMC3004768
DOI:
10.1016/j.molcel.2010.10.030
[Indexed for MEDLINE]
Free PMC Article

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