Cited by 175Cancer, Hypoxia, and MetabolismEar and Head TumorsErythropoietin and Anemia Treatment

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The VHL Tumor Suppressor: Master Regulator of HIF

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Haase, Volker·2009·Current Pharmaceutical Design

DOI 10.2174/138161209789649394PMC PMC3622710

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Abstract

Hypoxia-Inducible Factors (HIFs) are heterodimeric oxygen-sensitive basic helix-loop-helix transcription factors that play central roles in cellular adaptation to low oxygen environments. The von-Hippel Lindau tumor suppressor (pVHL) is the substrate recognition component of an E3 ubiquitin ligase and functions as a master regulator of HIF activity by targeting the hydroxylated HIF-alpha subunit for ubiquitylation and rapid proteasomal degradation under normoxic conditions. Mutations in pVHL can be found in familial and sporadic hemangioblastomas, clear cell carcinomas of the kidney, pheochromocytomas and inherited forms of erythrocytosis, illustrating the importance of disrupted molecular oxygen sensing in the pathogenesis of these diseases. Tissue-specific gene targeting of pVHL in mice has demonstrated that efficient execution of HIF proteolysis is critically important for normal tissue physiology, and has provided novel insights into the functional consequences of HIF activation on the cellular and tissue level. Here we focus on the contribution of individual HIF transcription factors to the development of VHL phenotypes and discuss how the pVHL/HIF axis could be exploited pharmacologically.

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Authors: Haase, V.
Affiliations: Vanderbilt University Medical Center (US)
Corresponding author: Haase, Volker
ORCID: Haase, Volker
Venue: Current Pharmaceutical Design
Publisher: Bentham Science Publishers Ltd.
Published: 2009-11-01
Volume: 15
Issue: 33
Pages: 3895-3903
ISSN: 1381-6128 (ISSN-L)
DOI: 10.2174/138161209789649394
PMC: PMC3622710
OpenAlex: W2067955850
Cited by: 175
References: 114
Citations by year: 2026: 5 · 2025: 27 · 2024: 19 · 2023: 21 · 2022: 20 · 2021: 18 · 2020: 10 · 2019: 9 · 2018: 5 · 2017: 4 · 2016: 9 · 2015: 5 · 2014: 8 · 2013: 6 · 2012: 5
FWCI: 1.01
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Current Pharmaceutical Design (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (R01CA100787)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080821, R01DK081646)
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 › Hematology › Erythropoietin and Anemia Treatment
Keywords: von Hippel-Lindau tumor suppressor, hypoxia-inducible factor, ubiquitin ligase, proteasomal degradation, oxygen sensing, hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma, erythrocytosis, HIF-targeted therapy
MeSH terms: Animals, Humans, Mutation, Phenotype, Drug Delivery Systems, Gene Targeting, Mice, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, Ubiquitination

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The VHL Tumor Suppressor: Master Regulator of HIF

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