Negative regulation of HIF-1α by an FBW7-mediated degradation pathway during hypoxia
Open accessAbstract
Hypoxia inducible factor-1α (HIF-1α) stimulates expression of genes associated with angiogenesis and is associated with poor outcomes in ovarian and other cancers. In normoxia, HIF-1α is ubiquitinated and degraded through the E3 ubiquitin ligase, von Hippel-Lindau; however, little is known about the regulation of HIF-1α in hypoxic conditions. FBW7 is an E3 ubiquitin ligase that recognizes proteins phosphorylated by glycogen synthase kinase 3β (GSK3β) and targets them for destruction. This study used an ovarian cancer cell model to test the hypothesis that HIF-1α phosphorylation by GSK3β in hypoxia leads to interaction with FBW7 and ubiquitin-dependent degradation. Expression of constitutively active GSK3β reduced HIF-1α protein and transcriptional activity and increased ubiquitination of HIF-1α in hypoxia, whereas pharmacologic inhibition of GSK3 or expression of siGSK3β promoted HIF-1α stabilization and activity. A mechanism through FBW7 was supported by the observed decrease in HIF-1α stabilization when FBW7 was overexpressed and both the elevation of HIF-1α levels and decrease in ubiquitinated HIF-1α when FBW7 was suppressed. Furthermore, HIF-1α associated with FBW7γ by co-immunoprecipitation, and the interaction was weakened by inhibition of GSK3 or mutation of GSK3β phosphorylation sites. The relevance of this pathway to angiogenic signaling was supported by the finding that endothelial cell tube maturation was increased by conditioned media from hypoxic SK-OV-3 cell lines expressing suppressed GSK3β or FBW7. These data introduce a new mechanism for regulation of HIF-1α during hypoxia that utilizes phosphorylation to target HIF-1α for ubiquitin-dependent degradation through FBW7 and may identify new targets in the regulation of angiogenesis.
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GSK-3β phosphorylates HIF-1α, leading to pVHL-independent ubiquitination and degradation; HIF-2α phosphorylation has not been demonstrated.
“Conversely, the serine-threonine kinase GSK-3β can phosphorylate HIF-1α (phosphorylation of HIF-2α has not been demonstrated), leading to pVHL-independent ubiquitination and degradation [18].”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [18]
The Introduction (page not provided) describes GSK3β phosphorylation of HIF-1α and VHL-independent degradation; the Discussion (page not provided) reports ubiquitin-dependent degradation through FBW7. The paper does not address whether HIF-2α phosphorylation has been demonstrated, so it does not support that part of the sentence. (LLM, conf=0.86)
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The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation
Acuña-Pilarte, K., & Koh, M. Y. (2025) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2025.06.005 · Cited by 41 · see citing works
- Authors
- Cassavaugh, J. M., Hale, S. A., Wellman, T. L., Howe, A. K., Wong, C., & Lounsbury, K. M.
- Affiliations
- University of Vermont (US)
- Corresponding author
- Lounsbury, Karen M.
- Venue
- Journal of Cellular Biochemistry
- Publisher
- Wiley
- Published
- 2011-10-22
- Volume
- 112
- Issue
- 12
- Pages
- 3882-3890
- ISSN
- 0730-2312 (ISSN-L)
- PMC
- PMC3202039
- OpenAlex
- W2170275592
- Cited by
- 88
- References
- 41
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 12 · 2022: 10 · 2021: 10 · 2020: 8 · 2019: 7 · 2018: 4 · 2017: 3 · 2016: 10 · 2015: 5 · 2014: 5 · 2013: 4 · 2012: 2
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cellular Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Washington
- University of Toronto
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL67352, T32HL007944, R01HL067351)
- National Institute of General Medical Sciences (R01GM097495)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- HIF-1α, FBXW7, glycogen synthase kinase-3β, protein phosphorylation, ubiquitin-mediated proteolysis, hypoxia, ovarian cancer, angiogenesis, endothelial tube formation, VHL, protein stability
- MeSH terms
- Glycogen Synthase Kinase 3 beta, F-Box-WD Repeat-Containing Protein 7, Female, Humans, Ovarian Neoplasms, Phosphorylation, Cell Hypoxia, Cell Cycle Proteins, Reverse Transcriptase Polymerase Chain Reaction, Glycogen Synthase Kinase 3, Ubiquitin-Protein Ligases, F-Box Proteins, Cell Line, Tumor, Hypoxia-Inducible Factor 1, alpha Subunit, Ubiquitination, Proteolysis
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