Roles and regulation of p53

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DESCRIPTION (provided by applicant): This is the second renewal of our Program Project that has been in existence for over 10 years and which has been highly productive and interactive. The goals of this program will be realized through an interdisciplinary and collaborative approach to understand the roles of mutant p53, p53 family member's p63 and p73 and new tumor suppressor genes in cancer. Our approaches include cell biology, proteomics, microscopy, bioinformatics, functional genomics, mouse modeling and human and mouse pathology. As this program has progressed, our research has become more translational and relevant to human disease, now focusing on breast, bladder and lymphoma tumor genesis. Carol Prives will employ the 3D culture protocol to examine the roles of mutant p53 and p53 homologues (P63 and p73) in mammary cell morphology and oncogenic transformation. She will also characterize the mechanisms of ANp63 protein turnover in these contexts. Arnold Levine will pursue the observation that breast cancer cells with mutant p53 have a stem cell gene expression signature, and will test mutant p53 allele-specific drugs that were identified by novel bioinformatic approaches for treatment of cancer cells. Levine will also study the roles of SNPs in p63 or p73 that influence DNA repair systems in female eggs and copy number variation that affect cancer in offspring Scott Lowe will continue to study the genetic and molecular basis of lymphoma. He will perform shRNA screens using the Ep-Myc B cell model to identify new tumor suppressor genes. He will also examine the role of genes co-deleted with p53 in lymphoma on chromosome 17p testing the hypothesis that such genes may also have tumor suppressive activity. Additionally Lowe will study the impact of reactivation of latent p53 by down-regulation of Mdm2, as well as perform an shRNA screen to identify genes whose inhibition facilitates death of mutant-p53 dependent tumors. Cordon-Cardo will focus on p63 expression and roles in normal and cancerous bladder tissue in mice and humans. He will use specific shRNAs to characterize the impact of p63 isoforms during urothelial development in mice, and determine the expression of p63 isoforms in bladder carcinoma. Cordon-Cardo will also pursue identification of bladder stem cells and the mechanisms by which they are chemoresistant. This program is highly dependent on the functioning of cores that support the administration, histopathology, shRNAs, mouse modeling and bioinfomatics that is required for the proposed experiments. The projects are even more interdependent and interactive than before and as a result much of the proposed research cannot be done effectively without the support of this program.