The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis

Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999)

Publication Language: English

Publication Type: Journal article, Letter

Publication year: 1999

Journal

Nature Nature Research

Book Volume: 399

Pages Range: 271-275

Issue: 6733

DOI: 10.1038/20459

Abstract

Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis and apoptosis1,2,3,4. The α subunits of HIF are rapidly degraded by the proteasome under normal conditions, but are stabilized by hypoxia5. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor6,7. Here we demonstrate a critical role for the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL in HIF-1 regulation. In VHL-defective cells, HIF α-subunits are constitutively stabilized and HIF-1 is activated. Re-expression of pVHL restored oxygen-dependent instability. pVHL and HIF α-subunits co-immunoprecipitate, and pVHL is present in the hypoxic HIF-1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF-1 is dissociated from pVHL. These findings indicate that the interaction between HIF-1 and pVHL is iron dependent, and thatit is necessary for the oxygen-dependent degradation of HIF α-subunits. Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours. The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing.

Authors with CRIS profile

Michael Wiesener

Additional Organisation(s)

Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

University of Oxford GB United Kingdom (GB) University of Birmingham GB United Kingdom (GB) John Radcliffe Hospital GB United Kingdom (GB)

How to cite

APA:

Maxwell, P.H., Wiesener, M.S., Chang, G.-W., Clifford, S.C., Vaux, E.C., Cockman, M.E.,... Ratcliffe, P.J. (1999). The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 399, 271-275. https://doi.org/10.1038/20459

MLA:

Maxwell, Patrick H., et al. "The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis." Nature 399 (1999): 271-275.

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