The VHL gene was located on the short arm of chromosome
3 (3p25–26) in 1988 then identified in 1993 [42,43]. Since its
identification, considerable insights have been made regarding the
functions of the VHL gene that now appears as a crucial gene influencing many cellular pathways. The best documented function of
the VHL protein (pVHL) is its critical role in targeting for proteosomal degradation the hypoxia inducible transcription factor
(HIF) [4,7]. This major role mainly contributes to angiogenesis and
tumorigenesis following inactivation of VHL gene [44]. Additionally,
pVHL has many HIF-independent functions that are also relevant
to tumor development, including maintenance of the primary cilium, regulation of extracellular matrix assembly, and regulation of
apoptosis in certain cell types