Role of TRRAP in the p53-Mediated Transcription of mdm2

描述(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。P53最具特征的转录靶点之一是MDM2癌基因，它在一些常见的人类癌症中过度表达。MDM2的转录激活在P53途径中是至关重要的，因为它的蛋白产物标记了P53蛋白小体介导的降解，从而提供了一个负反馈环。我们已经证明，ATM相关TRRAP蛋白的招募对于P53介导的MDM2转录激活是必不可少的。TRRAP是几个多蛋白乙酰转移酶复合体的组成部分，与转录调控和DNA修复有关。这项研究的目标包括：a.)定义哪些不同的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.)定义了TRRAP招募到MDM2启动子的分子后果，D.)映射MDM2中的独特元素促进了其对TRRAP的依赖。了解TRRAP复合体在P53生化活性中的作用将为我们提供对人类癌症中最频繁突变的途径的更深层次的分子洞察。

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.