Role of Malic Enzymes in Tumorigenesis

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DESCRIPTION (provided by applicant): This proposal aims to characterize the role of the tumor suppressor p53 in cellular metabolism and the consequence of losing this function in tumor pathogenesis. The tumor suppressor p53 is the most frequently mutated gene in human tumors. p53 induces various anti-proliferative processes in response to tumor- promoting stresses, and recent evidence indicated a critical role for p53-mediated metabolic regulation in tumor suppression. However, the p53-controlled metabolic genes that are important for tumor development are still unclear. In our preliminary studies, we found that p53 suppresses the expression of malic enzyme 1 (ME1) and malic enzyme 2 (ME2) genes. These enzymes catalyze the decarboxylation of malate - a tricarboxylic acid cycle (TCA cycle) intermediate - into the common TCA cycle carbon source pyruvate, and thus may have a regulatory role in matching TCA flux to cellular demand for energy, reducing equivalents, and biosynthetic precursors. We hypothesize that suppression of MEs by p53 is important for controlling metabolic activities required for cell proliferation, and that loss of this regulation due to p53 inactivation contributes to tumorigenesis. We propose three specific aims to determine the functions of MEs in metabolism, anti-oxidant response, and tumorigenesis, respectively. The proposed studies will lead to a better understanding of the links between metabolism and p53-mediated tumor suppression. They will also reveal metabolic alterations important for tumorigenesis and may identify valuable targets for tumor therapy.