Molecular Interactions and Regulation of p53

p53 的分子相互作用和调控

基本信息

批准号：
8288894
负责人：
Ming-Ming Zhou
金额：
$ 28.01万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8288894
关键词：
Acetylation Address Apoptosis Binding Biochemical Biological Bromodomain C-terminal CREB-binding protein Cell Cycle Arrest Cells Chemicals Chromatin DNA Damage Data EP300 gene Gene Targeting Genes Genetic Transcription Genotoxic Stress Goals HTATIP gene Health Histone Acetylation Human Human Biology In Vitro Individual Joints Lead Lysine MDM2 gene Malignant Neoplasms Mediating Methylation Modification Molecular PCAF gene Phosphorylation Play Post-Translational Protein Processing Protein p53 Proteins Recruitment Activity Regulation Reporting Role Site Specificity Stress Structure TP53 gene Testing Transcriptional Activation Transcriptional Regulation Tumor Suppression Ubiquitination base cancer therapy design histone modification human CREBBP protein in vivo Model novel oncoprotein p21 outcome forecast p53-binding protein response senescence small molecule transcription factor tumor

项目摘要

Site-specific post-translational modifications of human tumor suppressor p53 induced by stress play an important role in the activity of p53 as a transcription factor that regulates cell cycle arrest, senescence or apoptosis. The Iong-term goal of this Project 2, as a part of the PPG, is to seek mechanistic understanding of the molecular interactions and regulation of p53 in human biology and cancer. While multiple acetylation and methylation sites in p53 have been reported, specific effects of individual or combined modifications on p53 activity remain elusive. Preliminary data is presented involving a structure-based functional analysis of p53 supporting the notion that acetylation-induced p53 activation in response to DNA damage is involved in co-activator recruitment and subsequent histone acetylation required for target gene transcriptional activation. Our study specifically supports the notion that p53 recruitment of the co-activator CBP (CREB binding protein) requires association of the CBP bromodomain with p53 at acetylated lys[353]: a molecular interaction that is essential for p53-induced transcriptional activation of the cyclin-dependent kinase inhibitor p21, involved in (31 cell cycle arrest. We hypothesize therefore that distinct modifications of p53 including lysine acetylation and merhylation have differential effects on p53 functions in cells. We propose a multifaceted approach to address mechanistic underpinnings of p53 transcriptional activation with the emphasis on the role of post-translational modifications in p53 activation. The specific aims are (1) to elucidate molecular basis of these modification mediated molecular interactions of p53 with co-activators, and to develop small molecule chemical probes with structure-based design to functionally modulate p53 interactions; and (2) to determine the interplay between the co-activators CBP/p300 and p53 C-terminal domain in transcriptional regulation and tumor suppression of p53 using a variety of biochemical and cell biological approaches including the establishment of an in vivo model. The emerging results from our planned studies are expected to yield new mechanistic understanding of post-translational modifications in p53 function. Given the central role of p53 in cancer, these studies will have important implications for the prognosis and treatment of human tumors.

应激诱导的人肿瘤抑制因子 p53 的位点特异性翻译后修饰发挥着重要作用作为调节细胞周期停滞、衰老或的转录因子，p53 在其活性中发挥重要作用细胞凋亡。作为 PPG 的一部分，该项目 2 的长期目标是寻求机械理解 p53 在人类生物学和癌症中的分子相互作用和调节。当多重乙酰化 p53 中的甲基化位点和甲基化位点已被报道，单独或组合修饰对 p53 活性仍然难以捉摸。提供了初步数据，涉及基于结构的功能分析 p53 支持这一观点，即响应 DNA 损伤而乙酰化诱导的 p53 激活涉及靶基因转录所需的共激活剂招募和随后的组蛋白乙酰化激活。我们的研究特别支持这样的观点：p53 招募共激活剂 CBP (CREB 结合蛋白）需要 CBP 溴结构域与 p53 在乙酰化 lys[353] 处的关联：一种分子 p53 诱导的细胞周期蛋白依赖性激酶抑制剂转录激活所必需的相互作用 p21，参与 (31 细胞周期停滞。因此，我们假设 p53 的不同修饰包括赖氨酸乙酰化和甲基化对细胞中 p53 功能具有不同的影响。我们提出一个多方面的方法来解决p53转录激活的机制基础强调翻译后修饰在 p53 激活中的作用。具体目标是 (1) 阐明这些修饰介导的 p53 与共激活剂分子相互作用的分子基础，并开发基于结构设计的小分子化学探针，以功能性调节 p53 互动； (2) 确定共激活剂 CBP/p300 和 p53 C 端之间的相互作用使用多种生化和细胞研究 p53 的转录调控和肿瘤抑制结构域生物学方法，包括建立体内模型。我们的新成果计划中的研究预计将对翻译后修饰产生新的机制理解 p53 功能。鉴于 p53 在癌症中的核心作用，这些研究将对人类肿瘤的预后和治疗。