Induction of the von Hippel-Lindau tumor suppressor gene by late hypoxia limits HIF-1 expression.

Journal Article

Hypoxia-inducible factor (HIF) remains the central focus of oxygen sensing during hypoxia. HIF is a heterodimeric transcription factor consisting of an oxygen-regulated alpha- and a constitutively expressed beta subunit. The von Hippel-Lindau tumor suppressor (pVHL) is a component of the E3 ubiquitin ligase complex and targets HIF-alpha to proteasomal degradation, but also is known to exert a significant control on HIF transactivation activity. However, the understanding of the full interaction between HIF and pVHL has been hindered by a lack in the understanding of pVHL regulation. Here, we report that pVHL itself is induced in prolonged hypoxia in a kinetic that parallels the observed downregulation of HIF-1alpha protein under such conditions. In addition, we document direct HIF-1alpha binding to the VHL promoter and identify a functional hypoxia response element (HRE) within the VHL promoter. Such induction of pVHL in hypoxia furthermore has functional implications for the HIF dependent hypoxic response, implicating a physiologically relevant feedback mechanism. These results provide an intriguing model, whereby HIF self-regulates expression through VHL and highlight the role of pVHL as a unifying mechanism of HIF regulation.

Full Text

Duke Authors

Cited Authors

  • Karhausen, J; Kong, T; Narravula, S; Colgan, SP

Published Date

  • August 15, 2005

Published In

Volume / Issue

  • 95 / 6

Start / End Page

  • 1264 - 1275

PubMed ID

  • 15962286

International Standard Serial Number (ISSN)

  • 0730-2312

Digital Object Identifier (DOI)

  • 10.1002/jcb.20489

Language

  • eng

Conference Location

  • United States