Publisher: Bentham Science Publishers
E-ISSN: 1873-4286|15|33|3895-3903
ISSN: 1381-6128
Source: Current Pharmaceutical Design, Vol.15, Iss.33, 2009-11, pp. : 3895-3903
Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.
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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