von Hippel–Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2α signaling and splenic erythropoiesis
Open accessAbstract
The R200W mutation in the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL) is unique in that it is not associated with tumor development, but rather with Chuvash polycythemia, a heritable disease characterized by elevated hematocrit and increased serum levels of erythropoietin and VEGF. Previous studies have implicated hypoxia-inducible factor-1alpha (HIF-1alpha) signaling in this disorder, although the effects of this mutation on pVHL function are not fully understood. In order to explore the mechanisms underlying the development of this polycythemia, we generated mice homozygous for the R200W mutation (Vhl(R/R)). Vhl(R/R) mice developed polycythemia highly similar to the human disease. The activity of HIF proteins, specifically the HIF-2alpha isoform, was upregulated in ES cells and tissues from Vhl(R/R) mice. Furthermore, we observed a striking phenotype in Vhl(R/R) spleens, with greater numbers of erythroid progenitors and megakaryocytes and increased erythroid differentiation of Vhl(R/R) splenic cells in vitro. These findings suggest that enhanced expression of key HIF-2alpha genes promotes splenic erythropoiesis, resulting in the development of polycythemia in Vhl(R/R) mice. This mouse model is a faithful recapitulation of this VHL-associated syndrome and represents a useful tool for studying polycythemias and investigating potential therapeutics.
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The ability of the R200W VHL species to capture hydroxylated HIF-α for ubiquitylation and subsequent proteasomal degradation is impaired.
“The ability of the R200W VHL species to capture hydroxylated HIF-α for ubiquitylation and subsequent proteasomal degradation is impaired”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [138]
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Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression
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- Authors
- Hickey, M. M., Lam, J. C., Bezman, N. A., Rathmell, W. K., & Simon, M. C.
- Affiliations
- University of Pennsylvania (US)
- Howard Hughes Medical Institute (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Simon, M. Celeste
- Venue
- Journal of Clinical Investigation
- Published
- 2007-11-08
- Volume
- 117
- Issue
- 12
- Pages
- 3879-89
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2066197
- OpenAlex
- W2127781938
- Cited by
- 110
- References
- 7
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 5 · 2021: 2 · 2020: 6 · 2019: 6 · 2018: 3 · 2017: 2 · 2016: 11 · 2015: 4 · 2014: 8 · 2013: 13 · 2012: 8
- FWCI
- 6.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Cancer Research Institute
- National Institutes of Health
- Directorate for Biological Sciences
- U.S. Public Health Service (66310)
- National Cancer Institute (K08CA098410, R01CA121781)
- Abramson Family Cancer Research Institute
- Topics
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Keywords
- von Hippel-Lindau protein, Chuvash polycythemia, HIF-2α, HIF-1α, splenic erythropoiesis, erythropoietin, vascular endothelial growth factor, erythroid progenitor cells, megakaryocytes, mouse model, tumor suppressor
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Disease Models, Animal, Erythropoiesis, Erythropoietin, Hematopoiesis, Extramedullary, Humans, Megakaryocytes, Mice, Mutant Strains, Polycythemia, Spleen, Signal Transduction, Amino Acid Substitution, Mutation, Missense, Genetic Diseases, Inborn, Vascular Endothelial Growth Factors, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Von Hippel-Lindau Tumor Suppressor Protein
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