The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.
Maxwell, Patrick H.; Wiesener, Michael S.; Chang, Gin-Wen; Clifford, Steven C.; Vaux, Emma C.; Cockman, Matthew E.; Wykoff, Charles C.; Pugh, Christopher W.; Maher, Eamonn R.; Ratcliffe, Peter J.
[Letter]
Nature.
399(6733):271-275, May 20, 1999.
(Format: HTML)
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 apoptosis [1-4]. The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions, but are stabilized by hypoxia [5]. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor [6,7]. 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 alpha-subunits are constitutively stabilized and HIF-1 is activated. Re-expression of pVHL restored oxygen-dependent instability. pVHL and HIF alpha-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 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 tumours. The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing.
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