Abstract
Inheritance of a faulty von Hippel-Lindau (VHL) tumor suppressor gene is the cause of VHL disease, a rare multisystemic autosomal dominant disorder characterized by the development of hypervascular tumors in a number of organs, including the retina, brain, spine, pancreas, adrenal gland, and the kidney. Recent discoveries have demonstrated that the VHL gene product pVHL serves as a substrate-recognition component of an E3 ubiquitin ligase complex that targets hypoxia-inducible factor (HIF) transcription factor for polyubiquitination and subsequent degradation. Accordingly, tumor cells devoid of functional pVHL show an inappropriate accumulation of HIF, as well as downstream HIF-target genes, such as vascular endothelial growth factor (VEGF), a potent angiogenic factor. Furthermore, HIF has been found to be elevated in many human cancers further underscoring its common significance in oncogenesis. These and other related recent findings have shed significant insight into the mechanisms governing mammalian cellular oxygen homeostasis and how disruptions in this oxygen-sensing pathway can lead to tumorigenesis. Next generation anti-cancer drugs will undoubtedly emerge from our understanding of the molecular pathways governing normal cellular metabolism, growth and differentiation that have gone awry during neoplastic transformation, and studies in VHL disease will serve as one of the proving grounds for the efficacy of designer anti-cancer drugs tailored against the VHL-HIF pathway.
Keywords: vhl, hif, rcc, e ubiquitin ligase, oxygen sensing
Current Cancer Drug Targets
Title: Molecular Targets from VHL Studies into the Oxygen-Sensing Pathway
Volume: 5 Issue: 5
Author(s): M. A. Maynard and M. Ohh
Affiliation:
Keywords: vhl, hif, rcc, e ubiquitin ligase, oxygen sensing
Abstract: Inheritance of a faulty von Hippel-Lindau (VHL) tumor suppressor gene is the cause of VHL disease, a rare multisystemic autosomal dominant disorder characterized by the development of hypervascular tumors in a number of organs, including the retina, brain, spine, pancreas, adrenal gland, and the kidney. Recent discoveries have demonstrated that the VHL gene product pVHL serves as a substrate-recognition component of an E3 ubiquitin ligase complex that targets hypoxia-inducible factor (HIF) transcription factor for polyubiquitination and subsequent degradation. Accordingly, tumor cells devoid of functional pVHL show an inappropriate accumulation of HIF, as well as downstream HIF-target genes, such as vascular endothelial growth factor (VEGF), a potent angiogenic factor. Furthermore, HIF has been found to be elevated in many human cancers further underscoring its common significance in oncogenesis. These and other related recent findings have shed significant insight into the mechanisms governing mammalian cellular oxygen homeostasis and how disruptions in this oxygen-sensing pathway can lead to tumorigenesis. Next generation anti-cancer drugs will undoubtedly emerge from our understanding of the molecular pathways governing normal cellular metabolism, growth and differentiation that have gone awry during neoplastic transformation, and studies in VHL disease will serve as one of the proving grounds for the efficacy of designer anti-cancer drugs tailored against the VHL-HIF pathway.
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Cite this article as:
Maynard A. M. and Ohh M., Molecular Targets from VHL Studies into the Oxygen-Sensing Pathway, Current Cancer Drug Targets 2005; 5 (5) . https://dx.doi.org/10.2174/1568009054629672
DOI https://dx.doi.org/10.2174/1568009054629672 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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