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MTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1?.

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-1?) 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.

SUBMITTER: Cam H

PROVIDER: S-EPMC3004768 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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

Cam Hakan H Easton John B JB High Anthony A Houghton Peter J PJ

Molecular cell 20101101 4

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 h ...[more]

PMID: 21095582

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