Mechanism of regulation of the hypoxia‐inducible factor‐1α by the von Hippel‐Lindau tumor suppressor protein
Open accessAbstract
In normoxic cells the hypoxia-inducible factor-1 alpha (HIF-1 alpha) is rapidly degraded by the ubiquitin-proteasome pathway, and activation of HIF-1 alpha to a functional form requires protein stabilization. Here we show that the product of the von Hippel-Lindau (VHL) tumor suppressor gene mediated ubiquitylation and proteasomal degradation of HIF-1 alpha under normoxic conditions via interaction with the core of the oxygen-dependent degradation domain of HIF-1 alpha. The region of VHL mediating interaction with HIF-1 alpha overlapped with a putative macromolecular binding site observed within the crystal structure of VHL. This motif of VHL also represents a mutational hotspot in tumors, and one of these mutations impaired interaction with HIF-1 alpha and subsequent degradation. Interestingly, the VHL binding site within HIF-1 alpha overlapped with one of the minimal transactivation domains. Protection of HIF-1 alpha against degradation by VHL was a multistep mechanism, including hypoxia-induced nuclear translocation of HIF-1 alpha and an intranuclear hypoxia-dependent signal. VHL was not released from HIF-1 alpha during this process. Finally, stabilization of HIF-1 alpha protein levels per se did not totally bypass the need of the hypoxic signal for generating the transactivation response.
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Hydroxylation of HIF-α allows VHL to bind HIF-α and target it for proteasomal degradation.
“This hydroxylation event allows the von Hippel–Lindau tumor suppressor protein (VHL), the substrate recognition component of an E3 ubiquitin ligase complex, to bind to HIF-α and target it for proteasomal degradation”
From Hypoxic control of metastasis (2016) · cites this paper as [14]
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- Authors
- Tanimoto, K., Makino, Y., Pereira, T., & Poellinger, L.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Poellinger, Lorenz
- Venue
- The EMBO Journal
- Published
- 2000-08-15
- Volume
- 19
- Issue
- 16
- Pages
- 4298-4309
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC302039
- OpenAlex
- W1972032694
- Cited by
- 928
- References
- 30
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 50 · 2023: 20 · 2022: 30 · 2021: 40 · 2020: 30 · 2019: 23 · 2018: 22 · 2017: 29 · 2016: 25 · 2015: 30 · 2014: 39 · 2013: 29 · 2012: 26
- FWCI
- 25.13
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancerfonden
- Svenska Sällskapet för Medicinsk Forskning
- Japan Society for the Promotion of Science
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- hypoxia-inducible factor-1α, von Hippel-Lindau protein, VHL tumor suppressor, protein stabilization, ubiquitin-proteasome degradation, oxygen-dependent degradation domain, protein-protein interaction, VHL mutation, nuclear translocation, transcriptional activation, hypoxia signaling
- MeSH terms
- Amino Acid Sequence, Animals, Hypoxia, Binding Sites, Cell Line, Cysteine Endopeptidases, DNA-Binding Proteins, Fungal Proteins, Humans, Ligases, Luminescent Proteins, Models, Biological, Molecular Sequence Data, Multienzyme Complexes, Mutation, Nuclear Proteins, Oxygen, Plasmids, Precipitin Tests, Proteins, Transcription Factors, Transfection, Ubiquitins, Immunoblotting, Signal Transduction, Transcriptional Activation, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Crystallography, X-Ray, COS Cells, Tumor Suppressor Proteins, Saccharomyces cerevisiae Proteins, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Green Fluorescent Proteins, Hypoxia-Inducible Factor 1, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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