权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular Interactions and Regulation of p53

p53 的分子相互作用和调控

基本信息

批准号：
7896964
负责人：
Ming-Ming Zhou
金额：
$ 20.86万
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：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7896964
关键词：
Acetylation Address Affinity Apoptosis Binding Binding Proteins Biochemical Biological Biological Assay Bromodomain C-terminal CREB-binding protein Cell Cycle Arrest Cells Chemicals Chromatin Conflict (Psychology)Confusion DNA Damage Data EP300 gene Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genotoxic Stress Goals HTATIP gene Health Histone Acetylation Histones Human Human Biology In Vitro Individual Joints Lead Ligands Lysine MDM2 gene Malignant Neoplasms Mediating Methylation Modification Molecular Outcome PCAF gene Phosphorylation Play Post-Translational Protein Processing Protein p53 Proteins Recruitment Activity Regulation Reliance 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 improved in vivo in vivo Model mouse model novel oncoprotein p21 outcome forecast overexpression 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.

应激诱导人肿瘤抑制基因p53的位点特异性翻译后修饰