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Cited by 151Cancer, Hypoxia, and MetabolismEar and Head TumorsRenal cell carcinoma treatment

The VHL tumor suppressor and HIF: insights from genetic studies in mice

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Kapitsinou, P P, Haase, V H·2008·Cell Death & Differentiation
DOI 10.1038/sj.cdd.4402313PMC PMC3799983
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Abstract

The von Hippel-Lindau tumor suppressor gene product, pVHL, functions as the substrate recognition component of an E3-ubiquitin ligase, which targets the oxygen-sensitive alpha-subunit of hypoxia-inducible factor (HIF) for rapid proteasomal degradation under normoxic conditions and as such plays a central role in molecular oxygen sensing. Mutations in pVHL can be found in familial and sporadic clear cell carcinomas of the kidney, hemangioblastomas of the retina and central nervous system, and pheochromocytomas, underscoring its gatekeeper function in the pathogenesis of these tumors. Tissue-specific gene targeting of VHL in mice has demonstrated that efficient execution of pVHL-mediated HIF proteolysis under normoxia is fundamentally important for survival, proliferation, differentiation and normal physiology of many cell types, and has provided novel insights into the biological function of individual HIF transcription factors. In this review, we discuss the role of HIF in the development of the VHL phenotype.

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  • Loss-of-function mutations in VHL impair proteasomal degradation of hydroxylated HIF α subunits and result in constitutive HIF activation despite normoxia.

    “A clear causal link between HIF dysregulation and tumorigenesis is illustrated by loss of function mutations in von Hippel–Lindau (VHL), which impair proteasomal degradation of hydroxylated HIF α subunits and result in constitutive HIF activation despite normoxia [[222], [223], [224], [225]].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [222]

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References 137 · Cited by 151

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Authors
Kapitsinou, P. P., & Haase, V. H.
Affiliations
University of Pennsylvania (US)
Corresponding author
Haase, V H
ORCID
Venue
Cell Death & Differentiation
Publisher
Springer Science and Business Media LLC
Published
2008-01-25
Volume
15
Issue
4
Pages
650-659
ISSN
  • 1350-9047 (ISSN-L)
  • 1476-5403
DOI
10.1038/sj.cdd.4402313
PMC
PMC3799983
OpenAlex
W2073422719
Cited by
151
References
137
Citations by year
2026: 2 · 2025: 13 · 2024: 5 · 2023: 5 · 2022: 9 · 2021: 6 · 2020: 5 · 2019: 9 · 2018: 7 · 2017: 8 · 2016: 9 · 2015: 5 · 2014: 5 · 2013: 8 · 2012: 10
FWCI
1.08
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Cell Death and Differentiation (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Heart Association
  • National Cancer Institute (R01CA100787)
  • National Institute of Diabetes and Digestive and Kidney Diseases (K08DK002668, R21DK072037, R21DK073467)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Oncology › Ear and Head Tumors
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
Keywords
von Hippel-Lindau tumor suppressor, von Hippel-Lindau protein, hypoxia-inducible factor, E3 ubiquitin ligase, oxygen sensing, clear cell renal cell carcinoma, hemangioblastoma, pheochromocytoma, tumor suppressor function
MeSH terms
Endothelial PAS Domain-Containing Protein 1, Animals, Carcinoma, Renal Cell, Genotype, von Hippel-Lindau Disease, Humans, Kidney Neoplasms, Neoplasms, Phenotype, Gene Expression Regulation, Neoplastic, Germ-Line Mutation, Mice, Knockout, Gene Expression Regulation, Developmental, Ubiquitin-Protein Ligases, 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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