Mechanisms of Mitotic Activation of the ATM kinase

ATM 激酶有丝分裂激活的机制

基本信息

批准号：
8234167
负责人：
Sankar Mitra
金额：
$ 29.3万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-05 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8234167
关键词：
ATM Gene Mutation ATM Signaling Pathway ATM activation ATM function Alanine Ataxia Telangiectasia Ataxia-Telangiectasia-Mutated protein kinase Behavior Carcinogenesis Mechanism Cell Cycle Regulation Cell Death Cell Line Cells Chromosomes DNA Damage DNA Double Strand Break Data Disease Dissociation Exhibits Family Genetic Goals Human Hypersensitivity Immunodeficiency and Cancer In Vitro Indium Ionizing radiation Kinetochores Light Maintenance Malignant Neoplasms Mass Spectrum Analysis Mediating Mitosis Mitotic Mitotic Cell Cycle Mitotic/Spindle Checkpoint Molecular Mutate Names Peptides Phenotype Phosphorylation Phosphotransferases Play Predisposition Process Protein Kinase Proteins Regulation Regulatory Pathway Reporting Role Serine Signal Pathway Signal Transduction Signal Transduction Pathway Sister Chromatid Stimulus Transducers aurora B kinase base cancer therapy cell growth dimer in vivo insight irradiation monomer novel prevent reconstitution research study response sensor tumorigenesis

项目摘要

SUMMARY ATM, mutation of which leads to the human autosomal recessive disorder Ataxia- Telangiectasia (A-T), plays a critical role in maintaining genetic stability and preventing cancer formation. ATM is a PI-3 like kinase that functions as a sensor and signal transducer in DNA damage responses. Currently, most of the functional studies of ATM focus on its essential role in the cellular response to ionizing radiation-induced DNA double strand breaks. However, because of the complexity of A-T phenotypes and many of the A-T phenotypes can not be simply explained by the lack of an optimal DNA damage response, functions of ATM in the absence of DNA damage must be further examined. We have found that ATM was required for the activation of the spindle checkpoint, a process that protects against chromosome missegregation by delaying sister chromatid separation. Our preliminary data demonstrated that ATM was activated during mitosis in the absence of DNA damage. The mitosis-dependent activation of ATM requires functional Aurora-B. Furthermore we found that Aurora-B phosphorylated ATM at Ser1403 both in vitro and in vivo. In depth studies have found that Aurora-B associated with ATM during mitosis and ATM was required for the activity of Bub1. Further we found that ATM phosphorylated Bub1 (at Ser314) and Mad 1(at Ser214). Our general hypothesis in this proposal is that mitotic activation of ATM is governed by Aurora-B and has functional significance in regulation of the spindle checkpoint. Therefore we propose to study the mechanisms of mitotic activation of ATM and to dissect the ATM pathways in the spindle checkpoint. Three specific aims are proposed. Aim 1 will focus on investigate the molecular mechanism of the ATM activation. Aim 2 will study the role of ATM Ser1403 phosphorylation on mitotic progression and the spindle checkpoint. Aim 3 will focus on studying the functional significance of mitotic- dependent ATM phosphorylation of its downstream target. Our long-term goal of this project is to better understand the role of ATM in mitotic cell cycle control as a basis for providing insights into general mechanisms of carcinogenesis, cell growth and cell death. Dissecting the important role of ATM in mitosis may help understand many A-T phenotypes and find a cure for the disease.

概括 ATM，其突变导致人类常染色体隐性遗传疾病共济失调- 毛细血管扩张（A-T）在维持遗传稳定性和预防方面发挥着关键作用癌症的形成。 ATM 是一种类似 PI-3 的激酶，具有传感器和信号功能 DNA损伤反应中的传感器。目前，ATM的功能研究大多重点关注其在细胞对电离辐射诱导的 DNA 双倍反应中的重要作用链断裂。然而，由于 A-T 表型的复杂性以及许多 A-T 表型不能简单地用缺乏最佳 DNA 损伤反应来解释，必须进一步检查在没有 DNA 损伤的情况下 ATM 的功能。我们有发现主轴检查点的激活需要ATM，这个过程通过延迟姐妹染色单体分离来防止染色体错误分离。我们的初步数据表明，ATM 在有丝分裂过程中在缺乏 DNA损伤。 ATM 的有丝分裂依赖性激活需要功能性 Aurora-B。此外，我们发现 Aurora-B 在体外和体内都磷酸化了 Ser1403 处的 ATM 体内。深入研究发现 Aurora-B 与有丝分裂期间的 ATM 相关， Bub1 的活动需要 ATM。进一步我们发现ATM磷酸化Bub1 （位于 Ser314）和 Mad 1（位于 Ser214）。我们在这个提案中的一般假设是有丝分裂 ATM 的激活受 Aurora-B 控制，在调节主轴检查点。因此我们建议研究有丝分裂激活的机制 ATM 并剖析主轴检查点中的 ATM 路径。三个具体目标是建议的。目标1将重点研究ATM激活的分子机制。目标 2 将研究 ATM Ser1403 磷酸化对有丝分裂进展的作用以及主轴检查点。目标 3 将重点研究有丝分裂的功能意义其下游靶标的依赖性 ATM 磷酸化。我们的长期目标是该项目旨在更好地了解 ATM 在有丝分裂细胞周期控制中的作用，作为提供对致癌、细胞生长和细胞死亡的一般机制的见解。剖析 ATM 在有丝分裂中的重要作用可能有助于理解许多 A-T 表型并找到治疗该疾病的方法。