The Role of p53 and 14-3-3 in Genomic Instability

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DESCRIPTION (provided by applicant): Genomic instability is a hallmark of cancer and an enabling feature that facilitates tumor development and advancement to malignancy. The p53 tumor suppressor is known to play a major role in the stabilization of the genome. However, the mechanism by which p53 executes it's function as "guardian of the genome" is unclear. In preliminary studies we have determined that 14-3-3gamma, a protein known to interact with the p53 tumor suppressor, can cause a form of genomic instability that is manifested by endoreduplication and production of cells with > 4N DNA content. We have found that this activity occurs in cells that lack a functional p53, but does not occur in cells where p53 remains active. Because polyploidy is an unstable condition that precedes aneuploidy, we postulate that 14-3-3gamma may decrease genomic stability when present at elevated levels. In support of this it has been reported that 14-3-3 expression is elevated in lung cancer and our preliminary data indicates that 14-3-3gamma is one of the isoforms that is overexpressed in these tumors. Because 14-3-3gamma physically interacts with the p53 protein and because the 14-3-3gamma-mediated rereplication phenotype occurs in the absence of a functional p53 we hypothesize that p53 suppresses 14-3-3gamma's ability to cause genomic instability through a direct physical interaction between the two proteins. To test this we will determine 1) whether 14-3-3gamma causes endoreduplication by examining its affect on the function of cell cycle control proteins, initiation of DNA replication, and cell cycle checkpoints, 2) whether wild-type p53 can suppress the endoreduplication and whether this requires a direct physical interaction with 14-3-3gamma and 3) characterize 14-3-3 expression in human lung tumors.