Project 4: Roles and Regulation of Mutant p53 and p63 Isoforms in Urothelial Development and Bladder Cancer Progression Carlos Cordon-Cardo, M.D., Ph.D. Cumulative observations by our group led us to hypothesize that the molecular processes by which p53 and p63 regulate urothelial differentiation are causally linked to their role in bladder tumor initiation and progression. Our main objective is to define the critical functions of p53 and p63-isoforms in urothelial development, bladder cancer initiation and progression. For this purpose, we will use state-ofthe- art molecular pathology and genetic approaches utilizing in vitro cell-based assays and in vivo mouse models, validating significant findings in human normal and tumor bladder tissues.
The specific aims are:
Aim #1. Comprehensive analysis of p53 and p63-isoforms during urothelial development. We discovered that p63 is essential for urothelial differentiation, and that p63-null mice developed an abnormal mono-cellular layer urothelium. Prelimianry data supports that this layer is constituted of

Public Health Relevance

Understanding critical processes regulated by p53 family members implicated in urothelial development and bladder tumor initiation will enhance our search for urothelial stem cells and related bladder cancer stem cells. Our studies have significant translational implications through the definition of a novel urothelial histogenesis model based on p63-differentiation pathways, determining and validating the predictive nature of p53 and p63 alterations in bladder cancer, and identifying candidate bladder cancer stem cells. In sum, results from these studies will have far reaching implications regarding bladder cancer prognosis and establishing effective treatment, thus assisting in the implementation of

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Columbia University (N.Y.)
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