Mechanisms of Mitotic Activation of the ATM kinase

ATM 激酶有丝分裂激活的机制

• 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
• 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

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.

总结 ATM突变导致人类常染色体隐性遗传性共济失调- 毛细血管扩张症（A-T）在维持遗传稳定性和预防 癌症形成ATM是一种PI-3样激酶，作为传感器和信号 在DNA损伤反应中的转导。目前，对ATM的功能性研究， 重点是它在电离辐射诱导的DNA双链反应中的重要作用 链断裂。然而，由于A-T表型的复杂性和许多A-T表型的复杂性， 表型不能简单地用缺乏最佳DNA损伤反应来解释， 在没有DNA损伤的情况下ATM的功能必须进一步检查。我们有 发现ATM是激活纺锤体检查点所必需的，这个过程 通过延迟姐妹染色单体分离防止染色体错误分离。我们 初步数据表明，在有丝分裂过程中， 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在体外和体内都能使ATM的Ser1403磷酸化。 vivo.深入研究发现，Aurora-B在有丝分裂期间与ATM相关， Bub1的活性需要ATM。进一步我们发现ATM磷酸化Bub1 (at Ser314）和Mad 1（Ser214）。我们在这个建议中的一般假设是， ATM的激活受Aurora-B控制，在调节 纺锤体检查点因此，我们建议研究有丝分裂激活的机制 并在纺锤体检查点中剖析ATM通路。三个具体目标是 提出了目的1探讨ATM激活的分子机制. 目的2研究ATM Ser1403磷酸化在有丝分裂进程中的作用， 纺锤体检查点。目的3将着重研究有丝分裂- 依赖ATM磷酸化的下游目标。我们的长期目标是 项目是为了更好地了解ATM在有丝分裂细胞周期控制中的作用， 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 并找到治愈疾病的方法