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Keywords:

  • von Hippel–Lindau;
  • pVHL;
  • HIF;
  • hypoxia-inducible factor;
  • tumorigenesis;
  • renal cell carcinoma;
  • pheochromocytoma;
  • senescence;
  • cilia

Abstract

  • • 
    von Hippel–Lindau (VHL) disease
  • • 
    The VHL protein, pVHL
  • • 
    HIF-dependent pVHL functions
    • - 
      Hydroxylation of HIF
    • - 
      HIF is a key mediator of VHL defective tumorigenesis
    • - 
      HIF responsive genes
  • • 
    HIF-independent pVHL functions
    • - 
      Regulation of apoptosis
    • - 
      Control of cell senescence
    • - 
      Microtubule stabilization and maintenance of the primary cilium
    • - 
      Regulation of extracellular matrix formation
    • - 
      and cell – cell adhesion
  • • 
    pVHL and synthetic lethality
  • • 
    Conclusions

von Hippel–Lindau (VHL) disease is a hereditary cancer syndrome caused by inherited mutations that inactivate the VHL tumour suppressor gene. The VHL locus encodes pVHL, whose best studied function is to bind to and down-regulate the hypoxia-inducible factor (HIF) family of oxygen-dependent transcription factors. Early efforts have established the fundamental role of HIF in VHL-defective tumorigenesis and in particular renal cell carcinoma. However, recent findings have revealed an alternate side to the story, the HIF-independenttumour suppressor functions of pVHL. These include pVHL's ability to regulate apoptosis and senescence as well as its role in the maintenance of primary cilium and orchestrating the deposition of the extracellular matrix. To what extent these HIF-dependent and HIF-independent functions cooperate in VHL-defective tumorigenesis remains to be determined.