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Curr Pharm Des. 2009;15(33):3895-903.

The VHL tumor suppressor: master regulator of HIF.

Author information

1
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. volker.haase@vanderbilt.edu

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.

PMID:
19671042
PMCID:
PMC3622710
DOI:
10.2174/138161209789649394
[Indexed for MEDLINE]
Free PMC Article

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