VHL TUMOR SUPPRESSOR
GENE
Robert Stearman, Ph.D., Staff Scientist
Joseph Riss, Ph.D., Postdoctoral Fellow
Jodi Maranchie, M.D., Guest Researcher
James Vasselli, M.D., Guest Researcher
W. Marston Linehan, M.D., Collaborator, Urologic Oncology Branch, NCI
Our research 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 mediated by the ability of the pVHL ubiquitin-ligase complex to recognize hypoxia-inducible factors; thus, the complex targets the factors for degradation under normoxic but not hypoxic conditions. Another consequence of reintroduction of wild-type pVHL is that the cell’s ability to undergo branching morphogenesis and invasion of extracellular matrix is altered, primarily through the production of inhibitors of matrix metalloproteases.
Over the past year, a detailed study of the G1 to S-phase cyclins was completed. The results indicated that VHL-RCC cells display an altered regulation of cyclin D1 in response to growth factor withdrawal and hypoxia. Current literature strongly suggests that exposure to hypoxia generally inhibits cell proliferation. It has been hypothesized that the cellular response to hypoxia involves reversible cell cycle arrest characterized by dephosphorylation of Rb, loss of CDK activity, and decreased cyclin synthesis. However, it has been observed that hypoxia can actually induce certain cells in the kidney to proliferate, which is relevant to our findings. Our results suggest that pVHL mediates the hypoxia-regulated induction of cyclin D1 mRNA levels. This was observed only in VHL-negative tumor lines into which wild-type pVHL had been reintroduced. The overexpression of cyclin D1 that results from pVHL loss may be the mechanism by which this pathway is deregulated in the tumors. This, in turn, would explain why Rb loss is not seen in VHL-associated RCC. In no other cell line tested did hypoxia induce cyclin D1. An intriguing hypothesis is that pVHL can mediate hypoxia induction of cyclin D1 and inactivation of Rb in certain cell lineages only. Thus only these lineages would give rise to cancer upon VHL loss. While speculative, this idea provides a potential explanation as to why the loss of VHL, a ubiquitously expressed tumor suppressor gene, gives rise to such a limited range of human cancers.
PUBLICATIONS
- de
Paulsen N, Brychzy A, Fournier MC, Klausner RD, Gnarra JR, Pause A,
Lee S. Role of transforming growth factor-alpha in von Hippel-Lindau
(VHL)(-/-) clear cell renal carcinoma cell proliferation: a possible
mechanism coupling VHL tumor suppressor inactivation and tumorigenesis.
Proc Natl Acad Sci USA 2001;98:1387-1392.
- Phillips
JL, Ghadimi BM, Wangsa D, Padilla-Nash H, Worrell R, Hewitt S, Walther
M, Linehan WM, Klausner RD, Ried T. Molecular cytogenetic characterization
of early and late renal cell carcinomas in von Hippel-Lindau disease.
Genes Chromosomes Cancer 2001;31:1-9.