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Review
. 2008 Oct 1;113(7 Suppl):1768-78.
doi: 10.1002/cncr.23645.

The von Hippel-Lindau gene: turning discovery into therapy

Peter E Clark  1 , Michael S Cookson
Affiliations
Review

The von Hippel-Lindau gene: turning discovery into therapy

Peter E Clark et al. Cancer. .

Abstract

Mutations or aberrations of the von Hippel-Lindau gene are responsible for the hereditary neoplastic syndrome that bears the same name, as well as for the majority of sporadic clear cell renal cell carcinomas. The discovery of this gene and subsequent clarification of its mechanism of action have led to a series of targeted treatments for advanced kidney cancer and have dramatically changed how we manage this disease. The discovery of the VHL gene is a prime example of how discoveries at the bench can inform and revolutionize therapeutics at the bedside. In this review, the authors trace this illuminating tale, from the cloning of the VHL gene, to elucidating its biologic function, to the development of novel therapeutics that have dramatically changed the paradigm of managing advanced renal cell carcinoma.

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Figures

FIGURE 1
FIGURE 1
Normal biology of the VHL-HIF axis in the setting of (A) normoxia and (B) hypoxia. In normoxic conditions, HIFα is hydroxylated on specific proline residues by prolyl-hydroxylases. VHL acts as the sensor for these hydroxylated proline residues as part of the VHL-E3 ubiquitin ligase. This polyubiquitinates HIFα and marks it for degradation by the proteasome. In hypoxic conditions (or in the presence of aberrant VHL), HIFα is allowed to accumulate in the cell. (C) It associates with HIFβ, and this complex translocates to the nucleus and acts as a transcription factor binding to hypoxia response elements and up-regulating oxygen sensitive genes. These include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor alpha (TGFα), glucose transporter-1 (GLUT1), carbonic anhydrase IX (CA-IX), erythropoietin (EPO), and others. Examples of certain ligands’ receptors are given, including VEGF receptor (VEGFR), PDGF receptor (PDGFR), and the receptor for TNFα, epidermal growth factor receptor (EGFR). Shown is the downstream signaling for 1 of these receptors, VEGFR, including through the PI3 kinase (PI3K)/AKT/mTOR, p38 MAP kinase (p38MAPK), and RAS/RAF/MEK/ERK pathways. Examples of agents that impact on this cascade are given, and where they act on the pathway is shown.
FIGURE 2
FIGURE 2
This timeline graphically illustrates key events that led to discovery of the VHL gene, subsequent elucidation of its biology, and development of therapeutics for clear cell renal cell carcinoma (ccRCC).
See this image and copyright information in PMC

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