REGULATION OF P53 EXPRESSION BY THYMIDYLATE SYNTHASE

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The main goal of this project is to characterize novel molecular mechanisms for the translational regulation of p53 gene expression by thymidylate synthase (TS). The main hypothesis is that, TS, in its role as a key regulatory protein, can regulate the translation of not only its own TS mRNA but also the translation of various critical cellular RNAs that are involved in cell cycle-related events including cell growth and proliferation. I will specifically focus on characterizing the interaction between TS and the mRNA of the p53 tumor suppressor gene and to determine the biological consequence(s) of this p53 RNA-TS protein interaction. Specifically, l will determine whether the interaction between TS protein and p53 mRNA will result in the translational regulation of p53. As part of this aim, l propose to characterize the potential biological consequences of translational regulation of p53 by TS, as they relate to cell cycle control, apoptosis, and chemosensitivity. Finally, the trans-acting domain(s) on TS protein that are required for binding to the p53 mRNA will be characterized. In terms of basic biology, these studies should have direct relevance in that they will provide important new insights into an increasingly described mechanism by which cellular gene expression is controlled, namely that of translational regulation. Moreover, such detailed molecular studies may provide the framework for the rational design and development of new therapeutic approaches that can be used to prevent and/or overcome the development of cellular resistance to critical antineoplastic agents such as the fluoropyrimidines and the antifolates.