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

Hakan Cam, John B. Easton, Anthony High, Peter J. Houghton

Research output: Contribution to journalArticle

156 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)509-520
Number of pages12
JournalMolecular Cell
Volume40
Issue number4
DOIs
StatePublished - Nov 24 2010
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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