mTORC1 Signaling under Hypoxic Conditions Is Controlled by ATM-Dependent Phosphorylation of HIF-1α
Open accessAbstract
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.
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REDD involves phosphorylation of HIF-1α.
“The latter involves phosphorylation of HIF-1α (88), illustrating again the overlap between these pathways.”
From Placental Origins of Chronic Disease (2016) · cites this paper as [88]
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- Authors
- Cam, H., Easton, J. B., High, A., & Houghton, P. J.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Houghton, Peter J.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 40
- Issue
- 4
- Pages
- 509-520
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3004768
- OpenAlex
- W2004991378
- Cited by
- 266
- References
- 63
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 9 · 2023: 14 · 2022: 13 · 2021: 26 · 2020: 23 · 2019: 23 · 2018: 11 · 2017: 16 · 2016: 14 · 2015: 21 · 2014: 14 · 2013: 24 · 2012: 20
- FWCI
- 7.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (n01cm42216-11-0-1)
- National Cancer Institute (N01CM42216, N01-CM-91001-03, CA21675, N01 CM042216, R01CA077776, CA77776)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mTORC1 signaling, hypoxia, ATM, HIF-1α, ataxia telangiectasia, tumor hypoxia, pediatric solid tumors, carcinogenesis, cell growth regulation
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, DNA Damage, DNA-Binding Proteins, Enzyme Activation, Humans, Phosphorylation, Phosphoserine, Proteins, Transcription Factors, Signal Transduction, Cell Hypoxia, Tumor Suppressor Protein p53, Apoptosis, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Xenograft Model Antitumor Assays, Tumor Suppressor Proteins, Multiprotein Complexes, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases, Ataxia Telangiectasia Mutated Proteins
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