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

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

Open access
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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  • At moderate levels, ROS induce transcription of HIF1α and stabilize the encoded protein by inhibiting the iron-dependent prolyl 4-hydroxylase involved in its degradation.

    “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]

    The Results report that HIF-1α has a half-life of less than five minutes under normoxia, and that an iron chelator prolongs its half-life; the Discussion attributes its stabilization under hypoxia to reduced degradation through the ubiquitin–proteasome pathway. The paper does not establish that moderate ROS induce HIF-1α transcription or inhibit an iron-dependent prolyl 4-hydroxylase. Its five-minute measurement concerns protein half-life, not time to hydroxylation. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • One or more Fe-S centers is a likely source of O2•− within complex I, although the ubisemiquinone binding site or the flavin complex could also be sources.

    “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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Research works printed but not linked: 3

  1. [5]Wang, G. L., Jiang, B.-H., Rue, E. A. & Semenza, G. L. (1995) Proc. Natl. Acad. Sci. USA 92, 5510-5514.
  2. [20]Kallio, P. J., Pongratz, I., Gradin, K., McGuire, J. & Poellinger, L. (1997) Proc. Natl. Acad. Sci. USA 94, 5667-5672.
  3. [33]Ema, M., Taya, S., Yokotani, N., Sogawa, K., Matsuda, Y. & Fujii-Kuriyama, Y. (1997) Proc. Natl. Acad. Sci. USA 94, 42734278.

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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
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
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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