The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.
Regulation of hypoxia-inducible factor 1α is mediated by an O 2 -dependent degradation domain via the ubiquitin-proteasome pathway
Open accessAbstract
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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“at moderate levels, ROS induce transcription of HIF1α, the founding member of the family of hypoxia-induced factors, and stabilize the encoded protein, which is normally hydroxylated within less than 5 min, by inhibiting the activity of the iron-dependent prolyl 4-hydroxylase (PHD) involved in its degradation29.”
From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [29]
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“One or more of the Fe-S centers is a likely source (135, 160, 251), although the ubisemiquinone (QH•) binding site (143, 160, 200), or the flavin complex (216), per se, could also be sources”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [160]
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Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients
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The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180
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Metadata
- 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)
- 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
- 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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