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In vivo Analysis of ATM-Regulated Pathways

ATM 调节通路的体内分析

基本信息

批准号：
7995986
负责人：
Randal Scot Tibbetts
金额：
$ 23.67万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-19 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7995986
关键词：
ATM gene ATM wt Allele Apoptosis Ataxia Telangiectasia Ataxia-Telangiectasia-Mutated protein kinase Attenuated Back Binding Proteins Biochemical CHEK2 gene CREB-binding protein CSNK1A1 gene Cell Cycle Cell Cycle Checkpoint Cell Cycle Regulation Cells Circadian Rhythm Pathway Circadian Rhythms Collaborations Cues Cyclic AMP-Responsive DNA-Binding Protein DNA Binding DNA Damage DNA Repair Enzymes Future Gene Expression Gene Targeting Genetic Genotoxic Stress Glean Goals Grant In Vitro Laboratories Link Malignant Neoplasms Mammalian Cell Mediating Mediator of activation protein Metabolism Minor Modeling Modification Molecular Mutate Mutation Nature Nerve Degeneration Neurons Oncogene Proteins Outcome Paint Pathway interactions Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Physiological Physiology Play Predisposition Principal Investigator Protein Binding Protein Isoforms Protein Kinase Proteins RNA Interference Regulation Regulator Genes Role Serum Signal Transduction Signal Transduction Pathway Site Stimulus Stress Syndrome Testing Transcription Coactivator Work ataxia telangiectasia mutated protein base casein kinase casein kinase I cell growth chromatin immunoprecipitation human CREBBP protein in vivo inhibitor/antagonist insight interest novel programs promoter protein complex protein function relating to nervous system research study response small molecule transcription factor

项目摘要

DESCRIPTION (provided by applicant): The major objectives of this application are to: (i) functionally characterize a signal transduction pathway linking ATM (ataxia-telangiectasia-mutated) to the cyclic AMP response element-binding protein (CREB) transcription factor; and (ii) identify and functionally characterize novel ATM substrates. ATM is a DNA damage-activated protein kinase that is mutated in the genetic instability and neurodegeneration syndrome, ataxia-telangiectasia, whereas CREB is a neuroprotective transcription factor that regulates cell growth, metabolism, and survival. We have defined a new mode of CREB regulation whereby ATM and casein kinases 1 and 2 (CK1/CK2) collaboratively phosphorylate CREB on five clustered sites termed the RAX domain (co-Regulated ATM and Casein Kinase Sites) in response to genotoxic stress. Phosphorylation of CREB by ATM and CK1/CK2 inhibits the interaction between CREB and its coactivator, CREB-binding protein (CBP) suggesting that the ATM pathway may repress CREB transcriptional functions in response to DNA damage. The linkage between ATM and CREB is intriguing given the neuroprotective functions of both factors. In this proposal we will test the hypothesis that ATM plays a dual role in CREB regulation through suppression and stimulation of RAX domain phosphorylation in unperturbed and DNA-damaged cells, respectively. An important goal of the work is to define the upstream signals controlling CREB RAX domain phosphorylation in the absence of DNA damage and to elucidate the biochemical outcomes of its modification in intact cells. In addition, we will use information gleaned from the CREB phosphorylation paradigm to discover and functionally characterize protein substrates that are coordinately regulated by ATM and CK1/CK2 in response to DNA damage. These studies should yield fundamental insights into the mechanisms of ATM function and CREB regulation, and may alter current views of ATM signaling in response to DNA damage. The goal of this project is to understand the molecular basis for the neurodegeneration/cancer susceptibility syndrome, ataxia-telangiectasia (A-T), which is caused by mutations in the ATM gene. ATM is a critical regulator of cellular responses to DNA damage and the work proposed in this application will characterize a particularly important downstream target of ATM, termed CREB (cyclic AMP response element-binding protein), which is an important regulator of gene expression. We are specifically interested in examining whether deregulation of CREB contributes to the manifestation of A-T-related phenotypes, including cancer, and neuron demise.

描述（由申请人提供）：本申请的主要目的是：(i)功能表征连接ATM（失调性毛细血管扩张突变）与环AMP反应元件结合蛋白（CREB）转录因子的信号转导途径；以及（ii）鉴定和功能表征新型ATM基板。ATM是一种DNA损伤激活的蛋白激酶，在遗传不稳定和神经退行性综合征、共济失调毛细血管扩张症中发生突变，而CREB是一种调节细胞生长、代谢和存活的神经保护转录因子。我们已经定义了一种新的CREB调控模式，其中ATM和酪蛋白激酶1和2 （CK1/CK2）协同磷酸化CREB的五个聚集位点，称为RAX结构域（共同调节ATM和酪蛋白激酶位点），以响应基因毒性应激。ATM和CK1/CK2对CREB的磷酸化抑制了CREB与其协同激活因子CREB结合蛋白（CBP）之间的相互作用，这表明ATM途径可能在DNA损伤时抑制CREB的转录功能。ATM和CREB之间的联系是有趣的，因为这两个因素都具有神经保护功能。在本提案中，我们将验证ATM在未受干扰和dna损伤细胞中分别通过抑制和刺激RAX结构域磷酸化在CREB调节中发挥双重作用的假设。这项工作的一个重要目标是确定在没有DNA损伤的情况下控制CREB RAX结构域磷酸化的上游信号，并阐明其在完整细胞中的修饰的生化结果。此外，我们将使用从CREB磷酸化范式收集的信息来发现和功能表征由ATM和CK1/CK2协调调节的蛋白质底物，以响应DNA损伤。这些研究将为ATM功能和CREB调控机制提供基本见解，并可能改变目前对ATM信号响应DNA损伤的看法。该项目的目标是了解由ATM基因突变引起的神经变性/癌症易感性综合征共济失调-毛细血管扩张症（A-T）的分子基础。ATM是细胞对DNA损伤反应的关键调节因子，本应用中提出的工作将描述ATM的一个特别重要的下游靶标，称为CREB（环AMP反应元件结合蛋白），它是基因表达的重要调节因子。我们特别感兴趣的是检查CREB的解除管制是否有助于a - t相关表型的表现，包括癌症和神经元死亡。