P53 Signaling and Cellular Response after Stress

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DESCRIPTION (provided by applicant): In response to NOT-OD-09-058, NIH Announces the availability of Recovery Act Funds for Competitive Revision Applications, we propose a competing revision for the R01 grant CA070856 entitled, "p53 Signaling and Cellular Response After Stress." The p53 signaling pathway is the most commonly subverted pathway yet identified in human tumors. Completed and ongoing experiments funded by this grant have and will continue to test the hypothesis that p53 regulates cellular outcome after stress through transcriptional regulation of target genes that coordinate pathways of growth arrest, repair, and survival versus apoptosis. Three original aims are under pursuit: (1) To determine the role of novel p53 target gene products involved in regulating cell survival after stress (with focus on EDN2); (2) To determine the role of novel p53 target gene products involved in regulating cell sensitivity to genotoxic stress (with initial focus on RPS27L and ISG20L1); and (3) To determine the mechanisms involved in dictating constitutive versus stress-inducible regulation of target genes by p53 and it family members. We have made progress on all three aims as evidenced by publications; and, we will continue our characterization of select p53 target genes as proposed. However, a gene-at-a-time approach is limiting given that no single target gene can explain more than a fraction of the tumor suppressive activity of p53. Instead, p53 regulates the transcription of an extensive network of genes involved in diverse functions such as cell cycle arrest, apoptosis, senescence, and autophagy. The complexity of the p53 response extends beyond just its genomic binding profile, and is reflected by the existence of two p53 homologs (p63 and p73) that can physically and functionally interact with p53 and one another. We overlaid comprehensive p53 genomic binding site data with microarray expression data to generate a panel of novel, p53-regulated target genes. Further, we compared this panel of p53 target genes with similarly derived panels from our p63 and p73 analyses and determined which of the target genes have unique or shared regulation by other members of the p53 family. A critical next step is to filter this panel of genes and prioritize the order of subsequent analyses given the significant investment of time and resources required for the in depth characterization of each target gene product (i.e., antibody production, model systems, and translation to human disease). We propose a new aim that involves functional characterization of a panel of novel, p53 family target genes in physiologically relevant models systems using an efficient, high-throughput approach. This aim is an expanded area of investigation that will require recruitment of additional personnel as well as purchase of equipment and supplies, all actions that will stimulate the economy and expand our understanding of the most commonly subverted pathway yet identified in human tumors. PUBLIC HEALTH RELEVACNE: In response to AARA NOT-OD-09-058, Recovery Act Funds for Competitive Revision Applications, we propose a competing revision for the R01 grant CA070856 entitled, "p53 Signaling and Cellular Response After Stress." Completed and ongoing experiments funded by this grant have and will continue to test the hypothesis, through three specific aims, that p53 regulates cellular outcome after stress through transcriptional regulation of target genes that coordinate pathways of growth arrest, repair, and survival versus apoptosis. We propose a new aim that involves functional characterization of a panel of novel, p53 family target genes in physiologically relevant models systems using an efficient, high-throughput approach; this aim represents an expanded area of investigation that will require recruitment of additional personnel as well as purchase of equipment and supplies, all actions that will stimulate the economy and expand our understanding of the most commonly subverted pathway yet identified in human tumors.