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

Patrick H. Maxwell, Michael S. Wiesener, Gin-Wen Chang, Steven C. Clifford, Emma C. Vaux, Matthew E. Cockman, Charles C. Wykoff, Christopher W. Pugh, Eamonn R. Maher and Peter J. Ratcliffe ()
Additional contact information
Patrick H. Maxwell: Wellcome Trust Centre for Human Genetics
Michael S. Wiesener: Wellcome Trust Centre for Human Genetics
Gin-Wen Chang: Wellcome Trust Centre for Human Genetics
Steven C. Clifford: University of Birmingham
Emma C. Vaux: Institute of Molecular Medicine, John Radcliffe Hospital
Matthew E. Cockman: Institute of Molecular Medicine, John Radcliffe Hospital
Charles C. Wykoff: Institute of Molecular Medicine, John Radcliffe Hospital
Christopher W. Pugh: Institute of Molecular Medicine, John Radcliffe Hospital
Eamonn R. Maher: University of Birmingham
Peter J. Ratcliffe: Wellcome Trust Centre for Human Genetics

Nature, 1999, vol. 399, issue 6733, 271-275

Abstract: 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.

Date: 1999
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DOI: 10.1038/20459

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