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Failure to prolyl hydroxylate hypoxia‐inducible factor α phenocopies VHL inactivation in vivo
Open accessAbstract
Many functions have been assigned to the von Hippel-Lindau tumor suppressor gene product (pVHL), including targeting the alpha subunits of the heterodimeric transcription factor HIF (hypoxia-inducible factor) for destruction. The binding of pVHL to HIFalpha requires that HIFalpha be hydroxylated on one of two prolyl residues. We introduced HIF1alpha and HIF2alpha variants that cannot be hydroxylated on these sites into the ubiquitously expressed ROSA26 locus along with a Lox-stop-Lox cassette that renders their expression Cre-dependent. Expression of the HIF2alpha variant in the skin and liver induced changes that were highly similar to those seen when pVHL is lost in these organs. Dual expression of the HIF1alpha and HIF2alpha variants in liver, however, more closely phenocopied the changes seen after pVHL inactivation than did the HIF2alpha variant alone. Moreover, gene expression profiling confirmed that the genes regulated by HIF1alpha and HIF2alpha in the liver are overlapping but non-identical. Therefore, the pathological changes caused by pVHL inactivation in skin and liver are due largely to dysregulation of HIF target genes.
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“Over-expression of non-degradable HIF-2α in hepatocytes produced erythrocytosis, whereas over-expression of HIF-1α did not. 110”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [110]
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Metadata
- Authors
- Kim, W. Y., Safran, M., Buckley, M. R., Ebert, B. L., Glickman, J., Bosenberg, M., Regan, M., & Kaelin, W. G.
- Affiliations
- Brigham and Women's Hospital (US)
- Broad Institute (US)
- University of Vermont (US)
- Harvard University (US)
- Corresponding author
- Kaelin, William G
- ORCID
- Venue
- The EMBO Journal
- Published
- 2006-09-14
- Volume
- 25
- Issue
- 19
- Pages
- 4650-4662
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1589988
- OpenAlex
- W2097654747
- Cited by
- 235
- References
- 58
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 13 · 2023: 11 · 2022: 9 · 2021: 11 · 2020: 10 · 2019: 12 · 2018: 13 · 2017: 6 · 2016: 10 · 2015: 10 · 2014: 25 · 2013: 14 · 2012: 12
- FWCI
- 6.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Cancer Institute (T32CA009172)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Ear and Head Tumors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- von Hippel-Lindau tumor suppressor, hypoxia-inducible factor alpha, HIF-1α, HIF-2α, prolyl hydroxylation, phenocopy, Rosa26 locus, Cre-loxP system, liver, skin, HIF target genes, gene expression profiling, tumor suppressor inactivation
- MeSH terms
- Epidermal Cells, Endothelial PAS Domain-Containing Protein 1, Animals, Blood Vessels, Body Weight, Epidermis, Gene Expression Regulation, HeLa Cells, Humans, Hydroxylation, Liver, Mice, Inbred BALB C, Mice, Mutant Strains, Organ Size, Phenotype, Proline, Recombination, Genetic, Hepatocytes, Cell Proliferation, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit
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