Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome in which affected individuals are at risk to develop tumors in a number of organs, including the kidneys. VHL is estimated to occur in 1/36,000 live births and inheritance follows an autosomal dominant pattern with a penetrance from 80-90%. VHL patients are at-risk to develop bilateral, multifocal renal tumors and cysts as well as a variety of other phenotypes. The research in my lab has focused on understanding the molecular changes that kidney cells undergo as a result of loss of expression of the von Hippel-Lindau protein (pVHL). We are particularly intrigued by the pleiotropic nature of the effects caused by reintroduction of wild-type pVHL into renal clear cell carcinoma (RCC) lines that had previously lost pVHL expression. Loss of pVHL appears to result in the characteristic growth factor independence of transformed cells. Specifically, VHL- cells do not exit the cell cycle on growth factor withdrawal. In addition, the loss of pVHL alters the responsiveness of the cells to hypoxia and appears to be responsible for the characteristic production of the angiogenic factor VEGF. This regulation is through the ability of the pVHL ubiquitin-ligase complex to recognize the hypoxia inducible factors, targeting them for degradation under normoxic but not hypoxic conditions. Finally, reintroduction of wild-type pVHL alters the ability to undergo branching morphogenesis and invasion of extracellular matrix, primarily through the production of inhibitors of matrix metalo-proteases. Over the past year, a detailed study of the G1 to S-phase cyclins was completed. The results indicated that VHL- RCC cells have an altered regulation of cyclin D1 in response to growth factor withdrawal and hypoxia. Current literature strongly suggests that exposure to hypoxia generally inhibit cell proliferation. It has been hypothesized that the cellular response to hypoxia involves reversible cell cycle arrest characterized by dephosphorylated Rb, loss of CDK activity, and decreased cyclin synthesis. However, relevant to our findings, hypoxia can actually induce certain cells in the kidney to proliferate. Our results suggest that pVHL mediates the hypoxia-regulated induction of cyclin D1 mRNA levels. This was only observed in VHL-negative tumor lines into which wild-type pVHL had been reintroduced. The over-expression of cyclin D1 that results from pVHL loss may be the mechanism by which this pathway is deregulated in these tumors. This, in turn, would explain why Rb loss is not seen in VHL-associated RCC. No other cell line tested displayed hypoxia induction of cyclin D1. An intriguing hypothesis is that only certain cell lineages are capable of pVHL-mediated, hypoxia induction of cyclin D1. It would be only in these lineage's that the loss of pVHL would induce cyclin D1 and inactivate Rb. Thus only these lineages would give rise to cancer upon VHL loss. While speculative, this idea provides a potential explanation for why the loss of VHL, a ubiquitously expressed tumor suppressor gene, gives rise to such a limited range of human cancers.
