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p53 Regulation and Function in Renal Cell Carcinoma

Hazel E. Warburton¹, Mark Brady¹, Nikolina Vlatkovi¹, W. Marston Linehan³, Keith Parsons² and Mark T. Boyd¹

¹ MDM2/p53 Laboratory, Division of Surgery and Oncology, University of Liverpool; ² Department of Urology, Royal Liverpool University Hospital, Liverpool, United Kingdom; and ³ Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Mark Boyd, MDM2/p53 Laboratory, Division of Surgery and Oncology, University of Liverpool, 5th Floor UCD Building, Daulby Street, Liverpool, L69 3GA, United Kingdom. Phone: 151-706-4185; Fax: 151-706-5826; E-mail: mboyd{at}liverpool.ac.uk.

Loss of p53 function is a critical event in tumor evolution. This occurs through a range of molecular events, typically a missense p53 mutation followed by loss of heterozygosity. In many cancers, there is compelling evidence that cells that can compromise p53 function have a selective advantage. The situation in renal cell carcinoma is unclear. It has recently been suggested that p53 function is unusually compromised in renal carcinoma cells by a novel dominant, MDM2/p14^ARF-independent mechanism. This is hard to reconcile with other recent studies that have identified p53 as an important prognostic indicator. Indeed, one of these latter studies found that the best predictor of poor outcome was the presence of high levels of both p53 (usually indicative of p53 mutation) and MDM2. Thus, it is important that we gain a clearer understanding of the regulation of p53 and the role of MDM2 in renal cell cancer. To address this, we have investigated the transcriptional activity of p53 in a panel of renal cell carcinoma cell lines and the contribution of MDM2 and p14^ARF to p53 regulation. We have found that p53 is functional in p53 wild-type renal cell carcinoma cells and that this activity is significantly regulated by MDM2 and to a much lesser extent by p14^ARF. Moreover, following induction of DNA damage with UV, the p53 response in these cells is intact. Thus, future studies of renal cell carcinoma that focus on p53 and MDM2 and their role in determining disease outcome will be required to create a better understanding of this notoriously difficult to manage disease.

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