The Role of Phosphatase CL100/MKP1 in Human Cancer

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DESCRIPTION (provided by applicant): CL100/MKP1 is a member of the dual specificity protein phosphatase family that is able to dephosphorylate both the threonine and tyrosine residues on mitogen-activated protein (MAP) kinases, and thus plays a critical role in negatively regulating the activises of MAP kinases. CL100/MKP1 can also inhibit DNA damage-induced apoptosis. CL100/MKP1 is induced by a variety of stimuli including oxidative stress and growth factors. We have made the novel observation that CLt00tMKP1 is a transcriptional target of p53. The mechanism by which CL100/MKP1 is regulated, including the role of p53, and its relationship to human cancer remain to be determined. Our long-range goal is to understand the mechanisms of the signal transduction pathways in cancer cells and their role in chemosensitivity to chemotherapeutic drugs. The objective of this application is to study the role of the phosphatase CL100/MKP1 in p53-mediated cellular responses in human cancer. Exposure of cells to oxidative stress results in activation of p53, induction of CL100/MKP1, and activation of MJ_P kinases. These considerations suggest potential links among p53, CL100/MKP1, and MAP kinases. Understanding these links will provide insights into how the signal tranduction pathways interact. The novel aspect of our proposal is the potential cross talk between the p53 pathway and the MAPK pathway. The central hypothesis is that the dual phosphatase CL100/MKP1 is a mediator that links the p53 pathway to the MA,PK pathway. Our hypothesis is based on preliminary data produced in our laboratory showing that CL100tMKP1 is upregulated in a p53_ependent fashion. The rationale for the application is that, once the mechanism of p53-mediated regulation of CL100iMKP1 is known, modulation of this process may lead to the development of a novel strategy for cancer treatment. We will test our hypothesis and accomplish the objectives of this application by pursuing the following three specific aims: (1) Determine the regulation of CL100/MKP1 by p53; (2) Define the role of CL100fMKP1 in p53-mediated cell cycle regulation; and (3) Elucidate the role of CL100/MKP1 in p53-mediated apoptosis and chemosensitivity. Collectively, our studies will provide important and novel insights into the role of CL100/MKP1 in cell cycle and apoptosis control in human cancer.