REGULATION OF P53 EXPRESSION BY THYMIDYLATE SYNTHASE

本项目的主要目标是描述胸苷酸合成酶（TS）对p53基因表达的翻译调控的新分子机制。主要假设是，TS作为一种关键的调节蛋白，不仅可以调节其自身TS mRNA的翻译，还可以调节参与细胞周期相关事件（包括细胞生长和增殖）的各种关键细胞RNA的翻译。我将特别关注TS和p53肿瘤抑制基因的mRNA之间的相互作用，并确定这种p53 RNA-TS蛋白相互作用的生物学后果。具体地说，我将确定TS蛋白和p53 mRNA之间的相互作用是否会导致p53的翻译调控。作为这一目标的一部分，我建议表征的潜在生物学后果的翻译调节p53的TS，因为它们涉及到细胞周期控制，凋亡和化疗敏感性。最后，将表征TS蛋白上与p53 mRNA结合所需的反式作用结构域。在基础生物学方面，这些研究应该有直接的相关性，因为它们将提供重要的新的见解越来越多地描述细胞基因表达的控制机制，即翻译调控。此外，这种详细的分子研究可以为合理设计和开发新的治疗方法提供框架，所述新的治疗方法可以用于预防和/或克服细胞对关键抗肿瘤剂如氟嘧啶和抗叶酸剂的耐药性的发展。

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.