Regulation of Hypoxia-Inducible Factor 1α Expression and Function by the Mammalian Target of Rapamycin

Hudson, Christine C.; Liu, Mei; Chiang, Gary G.; Otterness, Diane M.; Loomis, Dawn C.; Kaper, Fiona; Giaccia, Amato J.; Abraham, Robert T.

doi:10.1128/mcb.22.20.7004-7014.2002

Cited by 1,186Cancer, Hypoxia, and MetabolismPI3K/AKT/mTOR signaling in cancerMetabolism, Diabetes, and Cancer

Regulation of Hypoxia-Inducible Factor 1α Expression and Function by the Mammalian Target of Rapamycin

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Hudson, Christine C., Liu, Mei, Chiang, Gary G., Otterness, Diane M., Loomis, Dawn C., Kaper, Fiona, Giaccia, Amato J., Abraham, Robert T.·2002·Molecular and Cellular Biology

DOI 10.1128/mcb.22.20.7004-7014.2002PMC PMC139825

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Abstract

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor containing an inducibly expressed HIF-1alpha subunit and a constititutively expressed HIF-1beta subunit. Under hypoxic conditions, the HIF-1alpha subunit accumulates due to a decrease in the rate of proteolytic degradation, and the resulting HIF-1alpha-HIF-1beta heterodimers undergo posttranslational modifications that promote transactivation. Recent studies suggest that amplified signaling through phosphoinositide 3-kinase, and its downstream target, mTOR, enhances HIF-1-dependent gene expression in certain cell types. In the present study, we have explored further the linkage between mTOR and HIF-1 in PC-3 prostate cancer cells treated with hypoxia or the hypoxia mimetic agent, CoCl(2). Pretreatment of PC-3 cells with the mTOR inhibitor, rapamycin, inhibited both the accumulation of HIF-1alpha and HIF-1-dependent transcription induced by hypoxia or CoCl(2). Transfection of these cells with wild-type mTOR enhanced HIF-1 activation by hypoxia or CoCl(2), while expression of a rapamycin-resistant mTOR mutant rendered both HIF-1alpha stabilization and HIF-1 transactivating function refractory to inhibition by rapamycin. Studies with GAL4-HIF-1alpha fusion proteins pinpointed the oxygen-dependent degradation domain as a critical target for the rapamycin-sensitive, mTOR-dependent signaling pathway leading to HIF-1alpha stabilization by CoCl(2). These studies position mTOR as an upstream activator of HIF-1 function in cancer cells and suggest that the antitumor activity of rapamycin is mediated, in part, through the inhibition of cellular responses to hypoxic stress.

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Several studies have shown that mTOR inhibition decreases HIF-1α and HIF-2α levels under both normoxic and hypoxic conditions.
“Consistent with this, several studies have shown that mTOR inhibition decreases HIF-1α and HIF-2α levels under both normoxic and hypoxic conditions (Hudson et al., 2002;Majumder et al., 2004;Thomas et al., 2006;Mohlin et al., 2015).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Hudson et al., 2002
The Results report that rapamycin inhibited basal HIF-1α expression in normoxic cells and hypoxia-induced HIF-1α accumulation. The passages do not establish the same effect for HIF-2α, so this paper supports only the HIF-1α part of the attributed claim. (LLM, conf=0.90)
Experimental — accuracy not yet measured
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”
From Hypoxic control of metastasis (2016) · cites this paper as [28]

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Authors: Hudson, C. C., Liu, M., Chiang, G. G., Otterness, D. M., Loomis, D. C., Kaper, F., Giaccia, A. J., & Abraham, R. T.
Affiliations: Duke Medical Center (US)
Sanford Burnham Prebys Medical Discovery Institute (US)
Stanford University (US)
Corresponding author: Abraham, Robert T.
ORCID: Chiang, Gary G.
Kaper, Fiona
Giaccia, Amato J.
Abraham, Robert T.
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 2002-10-01
Volume: 22
Issue: 20
Pages: 7004-7014
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.22.20.7004-7014.2002
PMC: PMC139825
OpenAlex: W2120129511
Cited by: 1,186
References: 52
Citations by year: 2026: 18 · 2025: 19 · 2024: 31 · 2023: 30 · 2022: 31 · 2021: 53 · 2020: 44 · 2019: 39 · 2018: 45 · 2017: 52 · 2016: 51 · 2015: 60 · 2014: 58 · 2013: 70 · 2012: 71
FWCI: 13.90
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Department of Defense
American Cancer Society
National Cancer Institute (P01CA067166, CA76193, R01CA076193, CA 67166)
DOD Prostate Cancer Research Program
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: HIF-1, HIF-1α, mTOR, rapamycin, hypoxia, cobalt chloride, oxygen-dependent degradation domain, prostate cancer, PC-3 cells, phosphoinositide 3-kinase signaling, HIF-1α stabilization, anticancer activity
MeSH terms: Phosphoinositide-3 Kinase Inhibitors, Chromones, Cobalt, DNA-Binding Proteins, Enzyme Inhibitors, Humans, Leupeptins, Monosaccharide Transport Proteins, Morpholines, Nuclear Proteins, Protein Kinases, Recombinant Fusion Proteins, Transcription Factors, Transcription, Genetic, Tumor Cells, Cultured, Transcriptional Activation, Cell Hypoxia, Helix-Loop-Helix Motifs, Sirolimus, Protein Kinase Inhibitors, Glucose Transporter Type 1, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases

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Regulation of Hypoxia-Inducible Factor 1α Expression and Function by the Mammalian Target of Rapamycin

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