Role of p53 Missense Mutations on Tumorigenesis in Vivo

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DESCRIPTION (provided by applicant): The p53 gene itself or other important components of the p53 pathway are altered in the genesis of most human cancers. In response to DNA damage signals or inappropriate oncogene activation, p53 levels increase and result in arrest of the cell cycle or induction of apoptosis, p53 surveillance thus prevents inappropriate DNA replication and cell division. Most studies have focused on understanding the mechanisms of apoptosis by p53 while the ability of p53 to induce the cell cycle arrest program has largely been ignored. During the previous funding period, we generated a mouse containing an arg-to-pro mutation at p53 amino acid 172, which distinguishes these pathways. Cells homozygous for the p53(515c) allele are unable to induce apoptosis, yet retain a partial cell cycle arrest pathway. Lymphomas and sarcomas develop in p53(515c) homozygous mice with much later latency than p53-null mice suggesting the importance of cell cycle arrest in tumor suppression. Importantly, tumors that develop in p53(515c)/(515c) mice remain diploid suggesting that the activities of this mutant p53 maintain genomic stability. The generation of these mice and cells from these mice will allow us to decipher the mechanism of genomic stability and the importance of this pathway in the genesis of tumors with other molecular defects. Specifically we will: 1) determine the molecular changes that cooperate with p53(515c)/(515c) in tumorigenesis; 2) examine survival and genomic stability in tumors from p53(515c)/- mice; 3) determine the importance of the cell cycle inhibitor and p53 target p21 in maintaining genomic stability and identify other targets of p53 important in arresting the cell cycle; 4) determine the ability of p53(515c)/(515c) mutant to inhibit c-myc induced tumors; and 5) determine the importance of p53(515c)/(515c) in delaying breast carcinomas in a different tumor prone strain of mice. This unique model will further our understanding of the role of p53 in cell cycle arrest and in maintaining genome stability.