Cited by 2,113Cancer, Hypoxia, and MetabolismErythropoietin and Anemia TreatmentUbiquitin and proteasome pathways

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Regulation of hypoxia-inducible factor 1α is mediated by an O 2 -dependent degradation domain via the ubiquitin-proteasome pathway

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Huang, L. Eric, Gu, Jie, Schau, Maureen, Bunn, H. Franklin·1998·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.95.14.7987PMC PMC20916

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Abstract

Hypoxia induces a group of physiologically important genes such as erythropoietin and vascular endothelial growth factor. These genes are transcriptionally up-regulated by hypoxia-inducible factor 1 (HIF-1), a global regulator that belongs to the basic helix-loop-helix PAS family. Although HIF-1 is a heterodimer composed of α and β subunits, its activity is primarily determined by hypoxia-induced stabilization of HIF-1α, which is otherwise rapidly degraded in oxygenated cells. We report the identification of an oxygen-dependent degradation (ODD) domain within HIF-1α that controls its degradation by the ubiquitin-proteasome pathway. The ODD domain consists of ≈200 amino acid residues, located in the central region of HIF-1α. Because portions of the domain independently confer degradation of HIF-1α, deletion of this entire region is required to give rise to a stable HIF-1α, capable of heterodimerization, DNA-binding, and transactivation in the absence of hypoxic signaling. Conversely, the ODD domain alone confers oxygen-dependent instability when fused to a stable protein, Gal4. Hence, the ODD domain plays a pivotal role for regulating HIF-1 activity and thereby may provide a means of controlling gene expression by changes in oxygen tension.

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Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.
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Authors: Huang, L. E., Gu, J., Schau, M., & Bunn, H. F.
Affiliations: Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
Brigham and Women's Hospital (US)
ORCID: Gu, Jie
Bunn, H. Franklin
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1998-07-07
Volume: 95
Issue: 14
Pages: 7987-7992
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.95.14.7987
PMC: PMC20916
OpenAlex: W2075054245
Cited by: 2,113
References: 40
Citations by year: 2026: 36 · 2025: 36 · 2024: 39 · 2023: 43 · 2022: 49 · 2021: 56 · 2020: 49 · 2019: 60 · 2018: 59 · 2017: 56 · 2016: 70 · 2015: 65 · 2014: 78 · 2013: 92 · 2012: 74
FWCI: 28.30
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK041234, R0-DK41234, F32-DK09365, F32DK009365)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: hypoxia-inducible factor-1α, oxygen-dependent degradation domain, ubiquitin-proteasome system, protein degradation, hypoxia, oxygen sensing, transcriptional regulation, erythropoietin, vascular endothelial growth factor
MeSH terms: Animals, Cell Line, Cysteine Endopeptidases, DNA, DNA-Binding Proteins, Multienzyme Complexes, Nuclear Proteins, Oxygen, Protein Binding, Transcription Factors, Ubiquitins, Signal Transduction, Cell Hypoxia, Dimerization, Proteasome Endopeptidase Complex, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit

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Regulation of hypoxia-inducible factor 1α is mediated by an O 2 -dependent degradation domain via the ubiquitin-proteasome pathway

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