title: mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α.
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.
authors.affiliation: Center for Childhood Cancer, Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Hakan
authors.initials: H
authors.lastname: Cam
authors.forename: John B
authors.initials: JB
authors.lastname: Easton
authors.forename: Anthony
authors.initials: A
authors.lastname: High
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
mesh_terms: D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D015687:Cell Hypoxia; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C469992:Ddit4 protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D010768:Phosphoserine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases