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来调节细胞对遗传损伤的反应。 mdm2 癌基因是 p53 最明确的转录靶标之一，它在许多常见的人类癌症中过度表达。 mdm2 的转录激活在 p53 通路中至关重要，因为它的蛋白质产物标记 p53 进行蛋白酶体介导的降解，从而提供负反馈环。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 是多种多蛋白乙酰转移酶复合物的组成部分，与转录调节和 DNA 修复有关。本研究的目标包括：a.) 确定 p53 功能需要哪些不同的 TRRAP 复合物，b.) 评估 TRRAP 依赖性的其他 p53 靶基因，c.) 确定 TRRAP 募集到 mdm2 启动子的分子后果，d.) 绘制 mdm2 启动子内赋予其 TRRAP 依赖性的独特元件。了解 TRRAP 复合物在 p53 生化活性中所起的作用应该可以让我们对人类癌症中最常见突变的途径有更深入的分子了解。

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.