The p53 tumor suppressor gene continues to hold distinction as the most frequently mutated gene in human cancer. The powerful selection for mutation of p53 in cancer is believed to result from its ability to induce programmed cell death (apoptosis). Evidence from several groups indicates that apoptosis induction by p53 does not rely on its best- characterized activity, transcriptional activation. This proposal seeks to characterize a new activity of p53, sequence-specific transcriptional repression. Wild type (wt) p53 induction in normal and tumor cells leads to transcriptional repression of Map4, which encodes a ubiquitously- expressed microtubule-polymerizing protein. Overexpression of Map4 in cells undergoing p53-dependent apoptosis delays the appearance of dying cells, verifying the importance of this process to apoptosis. In stably- transfected cells, the Map4 promoter can confer negative regulation by p53 to a heterologous gene. A fragment of this promoter can interact with wt but not mutant p53 protein in cell extracts. Recent data indicate that in addition to Map4, p53 represses other genes encoding components of microtubules. Elucidation of the mechanism of transcriptional repression by p53 is likely to be a critical step toward understanding tumor suppression by this protein. Understanding other targets genes of p53-mediated repression will also be important. This proposal seeks to achieve these goals.
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