Mechanisms of transcriptional regulation by mutant p53

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

PROJECT SUMMARY Mutation of the TP53 gene is frequent in human cancer with wild type (WT) p53 clearly being implicated as a tumor suppressor. A growing body of evidence now supports the notion that tumor-associated mutant p53 not only loses tumor suppressing activity, but also gains novel oncogenic roles. Although p53 has been shown to have cytoplasmic functions, its role in controlling gene expression is certainly central to both its WT tumor suppressing role and its mutant oncogenic function. The proposed research focuses on the transcriptional responses of p53 spanning from normal tissue with exclusively WT p53, through effects of missense mutant p53 in the presence of WT in the precancerous setting, to ultimately how mutant p53, in the absence of WT, results in metastatic cancer. Three specific aims are proposed. In the first aim, we will determine how missense mutation of one allele of p53 influences the remaining WT allele in the radiation response and tumorigenesis. Previous cell-based studies have supported the notion that in such heterozygous genotypes, the mutant exerts a dominant-negative effect on WT functions, relevant for tumor susceptibility disorders like Li-Fraumeni syndrome, which is associated with germline single allele p53 missense mutation. Our preliminary data examining the radiation response in vivo demonstrates that the m/+ genotype has an expanded transcriptome, suggesting a complex interplay between the two p53 alleles. In the second aim, the effect of missense mutation of p53 on basal gene expression and its contribution to tumorigenesis will be examined. We have shown that WT p53 occupies genes and regulate their basal expression. These basal targets are regulated in a distinct manner from those that are induced in stress responses that been well-studied in the past. Mutant p53 also regulates basal gene expression and there is a subset of genes that overlap between WT basal targets and those of mutant p53, which will be further explored. In the final aim, how mutant p53, in the absence of WT, contributes to metastasis will be studied. A murine model for metastatic progression of esophageal squamous cell carcinoma was developed by Project 3. Preliminary data shows altered gene occupancy and expression during the transition from primary tumor to metastasis with upregulation of certain key targets: Csf1, Birc5, and Slc7a11. The biological roles of the first two are a focus of Project 3, while the latter is being studied by Project 2. Findings will then be explored in the context of a mouse model for pancreas cancer developed by Project 1. Given the essential role of transcriptional regulation in the activity of p53, it is postulated that downstream control of specific target genes are key determinants of cellular outcomes. The existence of gained oncogenic activity by tumor-associated mutant p53 thus provides the unexpected possibility for a targeted therapy involving a tumor suppressor.