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

Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, a ngiogenesis and apoptosis(1-4). The alpha subunits of HIF are rapidly degra ded by the proteasome under normal conditions, but are stabilized by hypoxi a(5). Cobaltous ions or iron chelators mimic hypoxia, indicating that the s timuli may interact through effects on a ferroprotein oxygen sensor(6,7). H ere we demonstrate a critical role for the von Hippel-Lindau (VHL) tumour s uppressor gene product pVHL in HIF-1 regulation. In VHL-defective cells, HI F alpha-subunits are constitutively stabilized and HIF-1 is activated. Re-e xpression of pVHL restored oxygen-dependent instability. pVHL and HIF alpha -subunits co-immunoprecipitate, and pVHL is present in the hypoxic HIF-1 DN A-binding complex. In cells exposed to iron chelation or cobaltous ions, HI F-1 is dissociated from pVHL. These findings indicate that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF alpha-subunits. Thus, constitutive HIF- 1 activation may underlie the angiogenic phenotype of VHL-associated tumour s. The pVHL/HIF-1 interaction provides a new focus for understanding cellul ar oxygen sensing.