Mechanisms of Mitotic Activation of the ATM kinase

ATM 激酶有丝分裂激活的机制

• 批准号: 7780410
• 负责人: BO XU
• 金额: $ 31.26万
• 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/7780410
• 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

DESCRIPTION (provided by applicant): 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 cannot 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.

描述（申请人提供）：ATM 的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症 (A-T)，在维持遗传稳定性和预防癌症形成方面发挥着关键作用。 ATM 是一种类似 PI-3 的激酶，在 DNA 损伤反应中充当传感器和信号转换器。目前，ATM 的大部分功能研究都集中在其在细胞对电离辐射引起的 DNA 双链断裂的反应中的重要作用。然而，由于 A-T 表型的复杂性，并且许多 A-T 表型不能简单地用缺乏最佳 DNA 损伤反应来解释，因此必须进一步检查在没有 DNA 损伤的情况下 ATM 的功能。我们发现 ATM 是纺锤体检查点激活所必需的，该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，在没有 DNA 损伤的情况下，ATM 在有丝分裂过程中被激活。 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 在体外和体内均使 ATM Ser1403 磷酸化。深入研究发现Aurora-B在有丝分裂过程中与ATM相关，而ATM是Bub1活性所必需的。进一步我们发现ATM磷酸化Bub1（Ser314）和Mad 1（Ser214）。我们在此提议中的一般假设是 ATM 的有丝分裂激活由 Aurora-B 控制，并且在纺锤体检查点的调节中具有功能意义。因此，我们建议研究 ATM 有丝分裂激活的机制，并剖析纺锤体检查点中的 ATM 通路。提出了三个具体目标。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程和纺锤体检查点的作用。目标 3 将重点研究其下游靶标的有丝分裂依赖性 ATM 磷酸化的功能意义。我们该项目的长期目标是更好地了解 ATM 在有丝分裂细胞周期控制中的作用，作为深入了解致癌、细胞生长和细胞死亡的一般机制的基础。剖析 ATM 在有丝分裂中的重要作用可能有助于了解许多 A-T 表型并找到治疗该疾病的方法。