Mutant p53 in Tumorigenesis, Invasion, and Metastasis - PROGRAM SUMMARY The p53 protein has been extensively studied for its tumor suppressor activity in human cancer. Missense mutation of the TP53 gene is a common event in tumors. This contrasts with other tumor suppressors where deletion or loss of expression is more prevalent. Studies in genetically engineered mice have shown that knock- in of particular tumor-derived p53 mutations results in an altered tumor spectrum often accompanied by metastasis. Since this is not typically seen in p53-null mice, it has been proposed that mutant p53 not only has loss of tumor suppressor activity but in some cases gains oncogenic activity as well. Different tumor mutants of p53 behave in distinct manners in such assays adding to the complexity of the findings. In this Program led by James Manfredi, four integrated and significant Projects will address key aspects of mutant p53 and its control of the metastatic phenotype. Project 1, Systematic studies of mutant p53 allelic variation , led by Drs. Scott Lowe (Memorial Sloan Kettering Cancer Institute) and Francisco Sanchez-Rivera (Massachusetts Institute of Technology) will perform high-throughput cellular and molecular phenotyping of mutant TP53 alleles. Project 2 led by Dr. Wei Gu (Columbia University), Mechanisms of the hot-spot mutant p53R175H in tumor metastasis . centers on a novel protein-protein interaction involving mutant p53 that is selective for 175H. Project 3, “Defining the roles of mutant p53 and Mdm2 in invasion and metastasis”, led by Drs. Anil Rustgi and Carol Prives (Columbia University), emphasizes the study of the biological roles of mutant p53 as well as the Mdm2 protein in promoting invasion and metastasis. Project 4 led by Drs. James Manfredi and Emily Bernstein (Icahn School of Medicine at Mount Sinai), Mechanisms of transcriptional regulation by mutant p53 will examine transcriptional mechanisms for mutant p53 oncogenesis. One Shared Resource Core will support this effort. Core 1 (Leader: Emily Bernstein, Ph.D., Epigenomics of mutant p53) will perform essential next generation sequencing analyses with a specific focus on mutant p53 and the p53-associated cistrome and transcriptome. Targeting tumor suppressors as a therapeutic strategy has been challenging since it by its nature needs to rely on restoration of wild-type functions. The notion that mutant p53 has gain-of-function activity, most likely driven by protein-protein interactions raises the intriguing possibility that this oncogenic activity may eventually be targeted. Given the frequency of p53 mutation in human cancer, this is an exciting possibility.
