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Role of TRRAP in the p53-Mediated Transcription of mdm2

TRRAP 在 p53 介导的 mdm2 转录中的作用

基本信息

批准号：
7229476
负责人：
STEVEN B. MCMAHON
金额：
$ 26.16万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7229476
关键词：
Acetyltransferase Address Apoptosis Binding Binding Sites Biochemical Cell Cycle Cell Cycle Arrest Cells Cellular Stress Chromatin Chromatin Structure Complex DNA Binding DNA Damage DNA Repair DNA-Directed RNA Polymerase Data Dependence Depth Elements Enzymes Event Family Feedback Gene Targeting Genes Genetic Genetic Transcription Goals Histone Acetylation Histone Deacetylase Histones Holoenzymes Human In Vitro Individual Lesion Lysine Malignant Neoplasms Maps Mediating Molecular Mutate Normal Cell Nucleosomes Numbers Oncogenes Pathway interactions Physiological Play Polymerase Positioning Attribute Post-Translational Protein Processing Protein Binding Protein Overexpression Protein p53 Proteins Reaction Recruitment Activity Reporting Role Structure Study Section TATA-Binding Protein Associated Factors TATA-Box Binding Protein TP53 gene TRRAP gene TRRAP protein Tail Therapeutic Intervention Transactivation Transcriptional Activation Transcriptional Regulation cancer cell cofactor design histone acetyltransferase in vivo insight multicatalytic endopeptidase complex promoter repaired response transcription factor tumor ubiquitin-protein ligase

项目摘要

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.

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。