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序列特异性转录因子的功能调节细胞对遗传损伤的反应。在p53的最充分表征的转录靶点中，是mdm2癌基因，其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，因为其蛋白产物标记p53用于蛋白体介导的降解，从而提供负反馈环。我们已经表明，ATM相关的TRRAP蛋白的招聘是必不可少的p53介导的激活mdm2转录。TRRAP是涉及转录调节和DNA修复的几种多蛋白乙酰转移酶复合物的组分。本研究的主要目的是：a.）定义p53功能所需的不同TRRAP复合物，B.）评估其他p53靶基因的TRRAP依赖性，c.）定义TRRAP募集至mdm2启动子的分子后果，d.）在mdm2启动子内定位赋予其TRRAP依赖性的独特元件。了解TRRAP复合物在p53生物化学活性中的作用应该为我们提供更深入的分子洞察力，以了解人类癌症中最常见的突变途径。

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.