Role of TRRAP in the p53-Mediated Transcription of mdm2

描述（由申请人提供）：p53肿瘤抑制因子通过其作为序列特异性转录因子的功能调节细胞对遗传损伤的反应。p53最具特征的转录靶点是mdm2致癌基因，它在许多常见的人类癌症中过表达。mdm2的转录激活在p53通路中是至关重要的，因为它的蛋白产物标志着p53进行蛋白体介导的降解，从而提供了一个负反馈回路。我们已经证明，atm相关TRRAP蛋白的募集对于p53介导的mdm2转录激活至关重要。TRRAP是几种多蛋白乙酰转移酶复合物的组成部分，涉及转录调节和DNA修复。本研究的目标包括：a.)确定哪些不同的TRRAP复合体是p53功能所必需的，b.)评估TRRAP依赖的其他p53靶基因，c.)确定TRRAP募集到mdm2启动子的分子后果，d.)绘制mdm2促进子中赋予其TRRAP依赖的独特元件。了解TRRAP复合物在p53的生化活性中所起的作用，将使我们对人类癌症中最常见的突变途径有更深入的分子认识。

DESCRIPTION (provided by applicant): The p53 tumor suppressor regulates the cellular response to genetic damage through its function as a sequence-specific transcription factor. Among the most well-characterized transcriptional targets of p53 is the mdm2 oncogene, which is overexpressed in a number of common human cancers. Transcriptional activation of mdm2 is critical in the p53 pathway because its protein product marks p53 for proteosome-mediated degradation, thereby providing a negative feedback loop. We have shown that recruitment of the ATM-related TRRAP protein is essential for p53-mediated activation of mdm2 transcription. TRRAP is a component of several, multi-protein acetyltransferase complexes implicated in both transcriptional regulation and DNA repair. Among the goals of this study are: a.) defining which of the distinct TRRAP complexes is required for p53 function, b.) assessing other p53 target genes for TRRAP dependence, c.) defining the molecular consequences of TRRAP recruitment to the mdm2 promoter, d.) mapping the unique elements within the mdm2 promote which confer its TRRAP dependence. Understanding the role that the TRRAP complexes play in the biochemical activity of p53 should provide us with a deeper molecular insight into the pathway mutated most frequently in human cancer.