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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.

应激诱导的人抑癌基因p53的翻译后位点特异性修饰 p53作为调节细胞周期停滞、衰老或凋亡的转录因子，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。而多重乙酰化和甲基化位点，单独或联合修饰对p53的特异性影响。 p53活性仍然难以捉摸。初步的数据，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损伤的反应参与了靶基因转录所需的辅激活因子募集和随后的组蛋白乙酰化 activation.我们的研究特别支持p53募集共激活因子CBP（CREB）的观点，结合蛋白）需要CBP布罗莫结构域与p53在乙酰化赖氨酸上的结合[353]：对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β 1细胞周期阻滞。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。我们提出了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与共激活剂的分子相互作用的分子基础，并开发具有基于结构设计的小分子化学探针以功能性调节p53 相互作用;和（2）确定共激活剂CBP/p300和p53 C-末端之间的相互作用使用多种生化和细胞技术，生物学方法，包括建立体内模型。我们的研究结果显示，计划中的研究有望产生对翻译后修饰的新的机制理解， p53功能。鉴于p53在癌症中的核心作用，这些研究将对癌症的治疗产生重要影响。人类肿瘤的预后和治疗。