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VHL, the story of a tumour suppressor gene

Abstract

Since the Von Hippel–Lindau (VHL) disease tumour suppressor gene VHL was identified in 1993 as the genetic basis for a rare disorder, it has proved to be of wide medical and scientific interest. VHL tumour suppressor protein (pVHL) plays a key part in cellular oxygen sensing by targeting hypoxia-inducible factors for ubiquitylation and proteasomal degradation. Early inactivation of VHL is commonly seen in clear-cell renal cell carcinoma (ccRCC), and insights gained from the functional analysis of pVHL have provided the foundation for the routine treatment of advanced-stage ccRCC with novel targeted therapies. However, recent sequencing studies have identified additional driver genes that are involved in the pathogenesis of ccRCC. As our understanding of the importance of VHL matures, it is timely to review progress from its initial description to current knowledge of VHL biology, as well as future prospects for novel medical treatments for VHL disease and ccRCC.

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Figure 1: History of research on the von Hippel–Lindau (VHL) gene.
Figure 2: Ribbon diagram illustrating the secondary structure of the pVHL–elongin C–elongin B complex.
Figure 3: Oxygen-dependent hypoxia-inducible factor regulation.

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Acknowledgements

The authors apologize to the many colleagues whose work could not cited because of space restraints. E.R.M. acknowledges support from a European Research Council Advanced Researcher Award and the National Institute for Health Research (NIHR) Biomedical Research Centre, Cambridge, UK.

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Correspondence to Eamonn R. Maher.

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T.E. owns shares with AstraZeneca and has attended advisory boards for Bayer, Pfizer, Roche, GSK and AVEO. He has corporate-sponsored research from AstraZeneca, GSK, Pfizer and Bayer, and received consultation fees from Roche, Bayer, Pfizer, GSK and AVEO. Recently, T.E. has taken part-time leave of absence from the University of Cambridge to act as Chief Clinician Scientist at AstraZeneca. L.G. and E.R.M. have no competing interests to declare.

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Gossage, L., Eisen, T. & Maher, E. VHL, the story of a tumour suppressor gene. Nat Rev Cancer 15, 55–64 (2015). https://doi.org/10.1038/nrc3844

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