P53-Mediated G1/M Checkpoint Controls Altered by PPM1D

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DESCRIPTION (provided by applicant): P53-Mediated G1/M Checkpoint Controls Altered by PPM1D The p53 tumor suppressor protein is a sequence-specific transcription factor that modulates the response of cells to genotoxic stress and other forms of cellular stress. PPM1D (formally called Wip1) is transcriptionally-activated in response to genotoxic stress in a p53-dependent manner. It encodes a protein phosphatase that targets the stress induced kinase p38MAPK which disrupts the p38MAPK-p53 signaling pathway. This is correlated with alterations in the pattern of N-terminal phosphorylation on p53 protein. N-terminal phosphorylation is important for p53 protein to function as a transcriptional factor. We and others have shown that forced exogenous expression of PPM1D attenuates the apoptotic response to DNA-damaging agents. Decreasing PPM1D in human tumor cells that constitutively over express it due to gene amplification enhances the apoptotic response to chemotherapeutic agents. This is correlated with changes, in the level of expression of the pro-apoptotic Bax gene.The goal of this project is to elucidate the mechanistic basis and the role that PPM1D plays in modulating the transcriptional activity of p53.The hypothesis to be tested is that disruption of the p38MAPK-p53 signaling pathway by PPM1D affects p53-mediated transcription of responsive genes involved in cell cycle checkpoint control and/or apoptosis. The Specific Aims are the following: 1) To determine if PPM1D-mediated disruption of p38MAPK-p53 signaling alters the interaction between p53 protein and p53-responsive elements of downstream target genes. 2) To determine if PPM1D-mediated disruption of p38MAPK-p53 signaling alters the interaction of p53 protein with transcriptional coactivators. 3) To identify and characterize genes whose expression is altered by PPM1D-mediated disruption of the p38MAPK-p53 signaling pathway. Lay Abstract: PPM1D is a new player in the p53 network about which we know very little at present. The PPM1D gene is often amplified in human breast, ovarian and neuroblastoma tumors that harbor a wild type p53 gene. This project will provide new information regarding the role that PPM1D plays in the p53 network involved in cell cycle control and apoptosis and elucidate the mechanistic basis for this action.