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

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.
Mesh Terms:
Animals, Apoptosis, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Cell Hypoxia, DNA Damage, DNA-Binding Proteins, Enzyme Activation, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Multiprotein Complexes, Phosphorylation, Phosphoserine, Protein-Serine-Threonine Kinases, Proteins, Signal Transduction, TOR Serine-Threonine Kinases, Transcription Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Xenograft Model Antitumor Assays
Mol. Cell
Date: Nov. 24, 2010
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