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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism*
  • Cell Hypoxia
  • DNA Damage
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes
  • Phosphorylation
  • Phosphoserine / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proteins / metabolism*
  • Signal Transduction*
  • TOR Serine-Threonine Kinases
  • Transcription Factors / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Ddit4 protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Multiprotein Complexes
  • Proteins
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Phosphoserine
  • TOR Serine-Threonine Kinases
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases