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:
- 金额:$ 23.67万
- 依托单位:
- 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:
- 关键词:ATM geneATM wt AlleleApoptosisAtaxia TelangiectasiaAtaxia-Telangiectasia-Mutated protein kinaseAttenuatedBackBinding ProteinsBiochemicalCHEK2 geneCREB-binding proteinCSNK1A1 geneCell CycleCell Cycle CheckpointCell Cycle RegulationCellsCircadian Rhythm PathwayCircadian RhythmsCollaborationsCuesCyclic AMP-Responsive DNA-Binding ProteinDNA BindingDNA DamageDNA RepairEnzymesFutureGene ExpressionGene TargetingGeneticGenotoxic StressGleanGoalsGrantIn VitroLaboratoriesLinkMalignant NeoplasmsMammalian CellMediatingMediator of activation proteinMetabolismMinorModelingModificationMolecularMutateMutationNatureNerve DegenerationNeuronsOncogene ProteinsOutcomePaintPathway interactionsPhenotypePhosphoric Monoester HydrolasesPhosphorylationPhosphorylation SitePhosphotransferasesPhysiologicalPhysiologyPlayPredispositionPrincipal InvestigatorProtein BindingProtein IsoformsProtein KinaseProteinsRNA InterferenceRegulationRegulator GenesRoleSerumSignal TransductionSignal Transduction PathwaySiteStimulusStressSyndromeTestingTranscription CoactivatorWorkataxia telangiectasia mutated proteinbasecasein kinasecasein kinase Icell growthchromatin immunoprecipitationhuman CREBBP proteinin vivoinhibitor/antagonistinsightinterestnovelprogramspromoterprotein complexprotein functionrelating to nervous systemresearch studyresponsesmall moleculetranscription 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):本申请的主要目标是:(i)在功能上表征了信号转导途径,将ATM(Ataxia-Telangiectasia-Mutated)连接到环状AMP响应元件结合蛋白(CREB)转录因子; (ii)识别并在功能上表征新型的ATM底物。 ATM是一种DNA损伤激活的蛋白激酶,在遗传不稳定性和神经退行性综合征,共济失调 - 链血管症中被突变,而CREB是一种神经保护因子,可调节细胞生长,代谢和存活率。我们已经定义了一种新的CREB调节模式,在该模式中,ATM和酪蛋白激酶1和2(CK1/CK2)在响应于遗传毒性应力的五个聚类的位点上合作地称为RAX结构域(共同调节的ATM和酪蛋白激酶位点)的磷酸化CREB。 ATM和CK1/CK2对CREB的磷酸化抑制了CREB与其共激活剂,CREB结合蛋白(CBP)之间的相互作用,这表明ATM途径可能会抑制CREB转录功能,以响应DNA损伤。鉴于这两个因素的神经保护功能,ATM和CREB之间的联系令人着迷。在此提案中,我们将通过抑制和刺激不受干扰和DNA损害的细胞中的RAX结构域磷酸化来检验ATM在CREB调节中起双重作用的假设。这项工作的一个重要目标是定义在没有DNA损伤的情况下控制CREB RAX域磷酸化的上游信号,并阐明其完整细胞中其修饰的生化结果。此外,我们将使用从CREB磷酸化范式中收集的信息发现并在功能上表征蛋白质底物,这些蛋白质底物是由ATM和CK1/CK2协同调节的,以响应DNA损伤。这些研究应对ATM功能和CREB调节的机制产生基本见解,并可能改变ATM信号的当前观点,以响应DNA损伤。该项目的目的是了解神经退行性综合征综合征,共济失调 - 甲状腺激素(A-T)的分子基础,这是由ATM基因突变引起的。 ATM是对DNA损伤的细胞反应的关键调节剂,本应用中提出的工作将表征ATM的特别重要的下游靶标,该目标称为CREB(环状AMP响应元件结合蛋白),这是基因表达的重要调节剂。我们特别有兴趣研究CREB的放松管制是否有助于与A-T相关的表型的表现,包括癌症和神经元灭亡。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Proteasome inhibition suppresses DNA-dependent protein kinase activation caused by camptothecin.
蛋白酶体抑制可抑制喜树碱引起的 DNA 依赖性蛋白激酶激活。
- DOI:10.1016/j.dnarep.2009.10.008
- 发表时间:2010
- 期刊:
- 影响因子:3.8
- 作者:Sakasai,Ryo;Teraoka,Hirobumi;Tibbetts,RandalS
- 通讯作者:Tibbetts,RandalS
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Randal Scot Tibbetts其他文献
Randal Scot Tibbetts的其他文献
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{{ truncateString('Randal Scot Tibbetts', 18)}}的其他基金
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Genetic enhancement of CREB signaling in Rett Syndrome
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Genetic analysis of UBQLN2-associated neurodegeneration in frontotemporal dementia
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10157746 - 财政年份:2020
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$ 23.67万 - 项目类别:
Mechanisms of mitochondrial damage in ataxia-telangiectasia
共济失调毛细血管扩张症线粒体损伤的机制
- 批准号:
9105821 - 财政年份:2015
- 资助金额:
$ 23.67万 - 项目类别:
Genome maintenance functions of CREB/ATF transcription factors
CREB/ATF转录因子的基因组维持功能
- 批准号:
8601387 - 财政年份:2013
- 资助金额:
$ 23.67万 - 项目类别:
Genome maintenance functions of CREB/ATF transcription factors
CREB/ATF转录因子的基因组维持功能
- 批准号:
8737817 - 财政年份:2013
- 资助金额:
$ 23.67万 - 项目类别:
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