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Loss of von Hippel–Lindau protein (pVHL) is known to contribute to the initiation and progression of tumours associated with VHL disease as well as certain sporadic tumours including clear cell renal cell carcinoma (ccRCC). The VHL gene was first identified and cloned over 20years ago and our understanding of its functions and effects has significantly increased since then. The best-known function of pVHL is its role in promoting the degradation of hypoxia-inducible factor α subunit (HIFα) as part of an E3 ubiquitin ligase complex. HIF stabilisation and transcriptional activation are also associated with various epigenetic alterations, indicating a potential role for VHL loss with changes in the epigenome. This review will highlight current knowledge regarding pVHL as well as discuss potentially novel roles of pVHL and how these may impact on cancer progression.

Hypoxia inducible factor-1alpha (HIF1alpha) plays a key role in the regulation of genes controlling oxygen supply, glucose metabolism and angiogenesis. Its expression in tumors appears to confer an adaptive advantage to their hypoxic microenvironment. We have evaluated the effect of the immunophilin ligands FK506 and cyclosporin A on HIF1alpha levels in different tumor cell lines. Our results indicate that both drugs are potent suppressors of HIF1alpha expression by accelerating the proteasomal degradation of the protein. Unexpectedly, the suppressive effect of these compounds was found to be independent of the presence of von Hippel Lindau factor and the degree of hydroxylation of the HIF1alpha protein. Moreover, HIF1alpha degradation induced by these compounds did not required ubiquitination, as it was also induced in E1 ligase-incompetent cells.

Synthesis and maintenance of primary cilia are regulated by the von Hippel–Lindau (VHL) tumour suppressor protein. Recent studies indicate that this regulation is linked to microtubule-dependent functions of pVHL such as orienting microtubule growth and increasing plus-end microtubule stability, however little is known how this occurs. We have identified the kinesin-2 motor complex, known to regulate cilia, as a novel and endogenous pVHL binding partner. The interaction with kinesin-2 facilitates pVHL binding to microtubules. These data suggest that microtubule-dependent functions of pVHL are influenced by kinesin-2.