A Novel Hypoxia-inducible Factor-independent Hypoxic Response Regulating Mammalian Target of Rapamycin and Its Targets

Arsham, Andrew M.; Howell, Jessica J.; Simon, M.Celeste

doi:10.1074/jbc.m212770200

Cited by 463PI3K/AKT/mTOR signaling in cancerCancer, Hypoxia, and MetabolismMetabolism, Diabetes, and Cancer

A Novel Hypoxia-inducible Factor-independent Hypoxic Response Regulating Mammalian Target of Rapamycin and Its Targets

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Arsham, Andrew M., Howell, Jessica J., Simon, M.Celeste·2003·Journal of Biological Chemistry

DOI 10.1074/jbc.m212770200

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Abstract

Hypoxia triggers a reversible inhibition of protein synthesis thought to be important for energy conservation in O2-deficient environments. The mammalian target of rapamycin (mTOR) pathway integrates multiple environmental cues to regulate translation in response to nutrient availability and stress, suggesting it as a candidate for O2 regulation. We show here that hypoxia rapidly and reversibly triggers hypophosphorylation of mTOR and its effectors 4E-BP1, p70S6K, rpS6, and eukaryotic initiation factor 4G. Hypoxic regulation of these translational control proteins is dominant to activation via multiple distinct signaling pathways such as insulin, amino acids, phorbol esters, and serum and is independent of Akt/protein kinase B and AMP-activated protein kinase phosphorylation, ATP levels, ATP:ADP ratios, and hypoxia-inducible factor-1 (HIF-1). Finally, hypoxia appears to repress phosphorylation of translational control proteins in a manner analogous to rapamycin and independent of phosphatase 2A (PP2A) activity. These data demonstrate a new mode of regulation of the mTOR pathway and position this pathway as a powerful point of control by O2 of cellular metabolism and energetics.

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Inactivating mutations in PTEN or TSC, as well as activating mutations in PI3K or AKT, lead to increased TORC1 activity that promotes HIF-α stabilization.
“Inactivating mutations in phosphatase and tensin homolog (PTEN) or the tuberosis sclerosis complex (TSC) complex, as well as activating mutations in phosphatidylinositol 3-kinase (PI3K) or AKT, lead to increased TORC1 activity that promotes HIF-α stabilization”
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Authors: Arsham, A. M., Howell, J. J., & Simon, M. C.
Affiliations: Howard Hughes Medical Institute (US)
Corresponding author: Simon, M.Celeste
ORCID: Arsham, Andrew M.
Howell, Jessica J.
Simon, M.Celeste
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2003-08
Volume: 278
Issue: 32
Pages: 29655-29660
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m212770200
OpenAlex: W1972558089
Cited by: 463
References: 65
Citations by year: 2026: 1 · 2025: 10 · 2024: 9 · 2023: 16 · 2022: 15 · 2021: 18 · 2020: 13 · 2019: 23 · 2018: 20 · 2017: 17 · 2016: 25 · 2015: 26 · 2014: 20 · 2013: 18 · 2012: 18
FWCI: 8.54
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 6269 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: U.S. Public Health Service (63310)
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: hypoxia, mTOR signaling, hypophosphorylation, translational regulation, 4E-BP1, p70S6K, ribosomal protein S6, eIF4G, protein synthesis inhibition, oxygen regulation, rapamycin, energy metabolism
MeSH terms: Adenosine Diphosphate, Adenosine Triphosphate, Hypoxia, Carrier Proteins, Cell Line, DNA-Binding Proteins, Dose-Response Relationship, Drug, Gene Expression Regulation, Humans, Nuclear Proteins, Oxygen, Phosphoproteins, Phosphorylation, Protein Kinases, Time Factors, Transcription Factors, Protein Biosynthesis, Blotting, Western, Signal Transduction, Cell Cycle Proteins, Ribosomal Protein S6, Ribosomal Protein S6 Kinases, 70-kDa, Eukaryotic Initiation Factor-4G, Adaptor Proteins, Signal Transducing, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases

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A Novel Hypoxia-inducible Factor-independent Hypoxic Response Regulating Mammalian Target of Rapamycin and Its Targets

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