Molecular Interactions and Regulation of p53

p53 的分子相互作用和调控

• 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
• 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

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.

压力引起的人类肿瘤抑制p53的特定地点的翻译后修饰 在p53作为调节细胞周期停滞，衰老或 凋亡。作为PPG的一部分，该项目2的IONG任期目标是寻求机械理解 人类生物学和癌症中p53的分子相互作用和调节。而多乙酰化 已经报道了p53中的甲基化位点，个人或联合修饰对 p53活性仍然难以捉摸。提供初步数据，涉及基于结构的功能分析 p53支持乙酰化​​诱导的p53激活对DNA损伤的激活与 靶基因转录所需的共激活因子和随后的组蛋白乙酰化 激活。我们的研究特别支持了p53共激活因子CBP的p53（CREB） 结合蛋白）需要将CBP溴结构域与乙酰化Lys的p53结合[353]：一种分子 对于p53诱导的细胞周期蛋白依赖性激酶抑制剂的转录激活至关重要的相互作用 p21，参与（31个细胞周期停滞。我们假设p53的明显修改包括 赖氨酸乙酰化和美旋化对细胞中p53功能具有不同的影响。我们提出了一个 多方面的方法来解决p53转录激活的机理基础的方法 强调翻译后修饰在p53激活中的作用。具体目的是（1） 这些修饰的分子基础介导了p53与共激活因子的分子相互作用， 并开发具有基于结构设计的小分子化学探针以调节p53 互动； （2）确定共激活器CBP/p300和p53 C端之间的相互作用 使用多种生化和细胞的转录调控和肿瘤抑制肿瘤抑制域 生物学方法，包括建立体内模型。我们的新兴结果来自我们 预计计划的研究将对翻译后修改产生新的机械理解 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。