This study is aimed at understanding the mechanism of action of the p53 tumor suppressor in its normal (wild type) and mutated forms. Inactivation of the endogenous wild type p53 is associated with over half of all cases of human cancer, making p53 the most frequent target for genetic alterations in human cancer. In many tumors, the inactivation of the wild type p53 occurs through point mutations within the protein coding region, which lead to the production of a full length mutant p53 protein. At least some of the mutant forms may actually gain a novel function which contributes to cancer development. The long-term goal of this project is to define the biochemical properties of wild type and mutant p53 which underlie each of their known biological activities. Given the frequent association of p53 alterations with human cancer, such information could eventually be valuable for devising new diagnostic and therapeutic strategies. Specifically, the work will try to establish a syngeneic mouse model for studying the gain of function by mutant p53. Once active mutants are clearly identified, an attempt will be made to look for genes whose expression is regulated by such mutants. Another part of the work will address the suggestion that mutant p53 can act in a negative dominant fashion, through the inactivation of co- expressed wild type p53. Specifically, the notion that such mutants can compete for limiting amounts of another protein will be tested by performing in vitro protein association assays. In addition, the possibility that p53 interacts with an SH3 domain protein, presumably at a cytoskeletal site, will be addressed. This will entail site directed mutagenesis in a putative SH3-binding domain of p53, on either a wild type or oncogenic mutant p53 background. The mutants will then be studied with respect to interactions with other cellular proteins, intracellular localization and biological activities. Further work will attempt to clone genes which are induced by wild type p53, and test whether their activation participates in mediating the anti-proliferative activities of wild type p53. Based on preliminary data, immunoglobulin promoters will also be tested as potential relevant p53 targets. Finally, some tumor cells shut off the p53 gene rather than mutating it. The possibility that such shut-off results from alterations in the transcriptional machinery will be probed.
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