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

We demonstrate a critical role for the von Hippel-Lindau tumour suppressor gene product pVHL in Hypoxia-inducible factor-1 regulation

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; Peter J. Ratcliffe


Scholarcy highlights

  • Hypoxia-inducible factor-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
  • 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
  • Constitutive HIF-1 activation may underlie the angiogenic phenotype of von Hippel-Lindau-associated tumours
  • The pVHL/Hypoxia-inducible factor-1 interaction provides a new focus for understanding cellular oxygen sensing

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