ATM (Ataxia Telangiectasia Mutated) signaling through cyclin D1
ATM(共济失调毛细血管扩张突变)通过细胞周期蛋白 D1 发出信号
基本信息
- 批准号:8045349
- 负责人:
- 金额:$ 19.23万
- 依托单位:
- 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:2010-04-01 至 2012-06-30
- 项目状态:已结题
- 来源:
- 关键词:ATM geneATM wt AlleleAddressAgingAlzheimer&aposs DiseaseAtaxiaAtaxia TelangiectasiaBiologicalBiologyBrainCell CycleCell Cycle CheckpointCell Cycle ProgressionCell Cycle RegulationCell DeathCellsChromosomal BreaksCyclin D1DNADNA DamageDNA RepairDNA damage checkpointDNA lesionDNA-dependent protein kinaseDiseaseEnvironmentFunctional disorderG1 PhaseGeneticGenome StabilityGenomic InstabilityGenomicsGenotoxic StressHumanHypersensitivityImmunologic Deficiency SyndromesInjection of therapeutic agentIonizing radiationKnockout MiceKnowledgeLesionMalignant NeoplasmsMediatingMetabolicMinorMitochondriaMitoticModelingMolecularMotorMotor AtaxiasMusNerve DegenerationNervous system structureNeurodegenerative DisordersNeuronal DifferentiationNeuronsOxidative StressParkinson DiseasePathogenesisPathway interactionsPhosphatidylinositolsPhosphorylationPhosphotransferasesPlayPredispositionProcessProliferatingProtein KinaseProtein-Serine-Threonine KinasesRadiation ToleranceReactive Oxygen SpeciesRegulationRoleSignal TransductionSourceStem cellsStrokeSymptomsTelangiectasisTestingTimeTumorigenicityataxia telangiectasia mutated proteinbasecopingdesigndisease-causing mutationinhibitor/antagonistloss of functionmembermouse modelnerve stem cellneural precursor cellneuron lossneutralizing antibodynovelprecursor cellpreventpublic health relevancerelating to nervous systemreproductiveresearch studyresponsesegregationsmall hairpin RNAtumor
项目摘要
DESCRIPTION (provided by applicant): Ataxia telangiectasia (AT) is an autosomal recessive disease caused by mutation in ataxia telangiectasia mutated (ATM) gene. ATM, a protein kinase, is activated by DAN double strand break and in turn it activates DNA repair and cell cycle checkpoint mechanisms to maintain genomic stability. The loss of these functions of ATM explains many symptoms of AT such as predisposition to cancer, radiation sensitivity, and immunodeficiency. However, it is not clear how ATM loss triggers neurodegeneration, which causes ataxia (motor dysfunction) in AT. We recently found that ATM induces destabilizing phosphorylation of cyclin D1 on the Thr286 residue, and suppresses cyclin D1 expression. We have also found that the suppression of cyclin D1 plays a critical role in inducing a G1 checkpoint following DNA damage. We will examine the roles of ATM and cyclin D1 in neuronal cell death induced by DNA damage. Metabolic demand in neurons is considered to generate high levels of reactive oxygen species which damage DNA. ATM senses such damage and would activate cell cycle checkpoint and DNA repair mechanism to cope with such endogenous genotoxic stress. We hypothesized that when ATM deficient neurons are exposed to genotoxic stress, cyclin D1 expression continues because its Thr286 residue is not phosphorylated. The high expression of cyclin D1 would override the G1 checkpoint and contribute to accumulation of DNA lesions in proliferating neural cells (Aim 1). In postmitotic neurons, high cyclin D1 expression would trigger aberrant cell cycle progression and cell death (Aim 2). In Aim 3, we will examine, if DNA lesions accumulated during proliferation would sensitize postmitotic neuron to DNA damaging treatment. Using primary neural cells from ATM-/- and +/+ mice, and human neural stem cells, we examine if ATM dependent cyclin D1 suppression protects neurons from oxidative stress. Biological consequence of genotoxic stress will be determined following manipulating the activity or expression of ATM and cyclin D1 using a specific inhibitor, shRNA or neutralizing antibody injection. The experiments are carefully designing to elucidate the validity of the novel concept that through its ability to control cyclin D1 expression, ATM plays a critical role in neuronal cells under genotoxic stress.
PUBLIC HEALTH RELEVANCE: We have found that under DNA damaging condition, ATM (ataxia telangiectasia mutated) controls cell cycle progression at least in part by its ability to target cyclin D1. Appling this new concept of ATM-cyclin D1 dependent cell cycle regulation to the biology of the neurons, this proposal will address molecular mechanism of degeneration of neurons in ataxia telangiectasia (AT). The finding obtained from these studies may advance our fundamental understanding on pathogenesis of AT, as well as other related neurodegenerative diseases, such as brain stroke, Parkinson disease, and Alzheimer's disease.
描述(由申请人提供):共济失调毛细血管扩张症(AT)是一种由共济失调毛细血管扩张症突变(ATM)基因突变引起的常染色体隐性遗传疾病。ATM是一种蛋白激酶,通过DAN双链断裂激活,进而激活DNA修复和细胞周期检查点机制以维持基因组稳定性。ATM这些功能的丧失解释了AT的许多症状,如癌症易感性、辐射敏感性和免疫缺陷。然而,目前尚不清楚ATM丢失如何触发神经变性,导致AT共济失调(运动功能障碍)。我们最近发现,ATM诱导Thr 286残基上的细胞周期蛋白D1的磷酸化失稳,并抑制细胞周期蛋白D1的表达。我们还发现,细胞周期蛋白D1的抑制在诱导DNA损伤后的G1检查点中起着关键作用。我们将研究ATM和细胞周期蛋白D1在DNA损伤诱导的神经细胞死亡中的作用。神经元中的代谢需求被认为会产生高水平的活性氧,从而损伤DNA。ATM感知到这种损伤,会激活细胞周期检查点和DNA修复机制来科普这种内源性遗传毒性应激。我们假设,当ATM缺陷的神经元暴露于遗传毒性应激,细胞周期蛋白D1的表达继续,因为它的Thr 286残基没有磷酸化。细胞周期蛋白D1的高表达将超越G1检查点,并有助于在增殖的神经细胞中积累DNA损伤(Aim 1)。在有丝分裂后的神经元中,细胞周期蛋白D1的高表达会引发异常的细胞周期进展和细胞死亡(目的2)。在目的3中,我们将检查增殖过程中积累的DNA损伤是否会使有丝分裂后神经元对DNA损伤治疗敏感。使用原代神经细胞从ATM-/-和+/+小鼠,和人类神经干细胞,我们研究ATM依赖性细胞周期蛋白D1抑制是否保护神经元免受氧化应激。在使用特异性抑制剂、shRNA或中和抗体注射操纵ATM和细胞周期蛋白D1的活性或表达后,将确定遗传毒性应激的生物学后果。这些实验是精心设计的,以阐明新概念的有效性,即通过其控制细胞周期蛋白D1表达的能力,ATM在遗传毒性应激下的神经细胞中起着至关重要的作用。
公共卫生相关性:我们已经发现,在DNA损伤条件下,ATM(共济失调毛细血管扩张症突变)控制细胞周期的进展,至少部分是通过它的目标细胞周期蛋白D1的能力。将ATM-cyclin D1依赖的细胞周期调控这一新概念应用于神经元的生物学研究,将有助于阐明共济失调毛细血管扩张症(AT)中神经元变性的分子机制。从这些研究中获得的发现可能会推进我们对AT以及其他相关神经退行性疾病(如脑卒中、帕金森病和阿尔茨海默病)的发病机制的基本理解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Masahiro Hitomi其他文献
Masahiro Hitomi的其他文献
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{{ truncateString('Masahiro Hitomi', 18)}}的其他基金
Asymmetric cell division drives therapeutic resistance and self-renewal in glioblastoma
不对称细胞分裂驱动胶质母细胞瘤的治疗抵抗和自我更新
- 批准号:
9305615 - 财政年份:2017
- 资助金额:
$ 19.23万 - 项目类别:
ATM (Ataxia Telangiectasia Mutated) signaling through cyclin D1
ATM(共济失调毛细血管扩张突变)通过细胞周期蛋白 D1 发出信号
- 批准号:
7896365 - 财政年份:2010
- 资助金额:
$ 19.23万 - 项目类别: