Antiapoptotic Role of Ataxia Telangiectasia and Rad3-Related

共济失调毛细血管扩张症和 Rad3 相关的抗凋亡作用

• 批准号: 8770880
• 负责人: Yue Zou
• 金额: $ 31.58万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8770880
• 关键词: ATM function; ATR protein kinase; Adopted; Apoptosis; Apoptotic; Ataxia Telangiectasia; BCL2 gene; Cardiovascular Diseases; Cell Cycle Progression; Cell Death; Cell Nucleus; Cell physiology; Cells; Cellular Stress; Cytoplasm; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA damage checkpoint; Development; Epidemiologic Studies; Exhibits; Exposure to; Family; Genome; Genome Stability; Genomic Instability; Genomics; Human; Isomerism; KRP protein; Knowledge; Laboratories; Link; Malignant Neoplasms; Mediating; Membrane Potentials; Mitochondria; Modification; Molecular; Molecular Conformation; Mutagens; NIMA; Neurodegenerative Disorders; Nuclear; Organism; Pathway interactions; Patients; Peptidylprolyl Isomerase; Phenotype; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Play; Principal Investigator; Protein Isoforms; Protein Kinase; Proteins; Regulation; Role; Signal Transduction; Stress; Testing; Therapeutic; Tumor Suppressor Proteins; UV Radiation Exposure; UV carcinogenesis; UV induced; ataxia telangiectasia mutated protein; base; cancer therapy; carcinogenesis; chemical carcinogen; human disease; innovation; irradiation; mitochondrial membrane; mouse model; novel; novel strategies; prevent; pro-apoptotic protein; promoter; public health relevance; response; sensor; tumor; ultraviolet damage; ultraviolet irradiation

DESCRIPTION (provided by applicant): DNA damage due to voluntary or involuntary exposure to various environmental genotoxic agents (e.g. irradiation and chemical carcinogens) is a major cause of human cancers and many other human diseases. In response to DNA damage, cells activate several major DNA damage response (DDR) pathways such as DNA damage checkpoints, DNA repair, and apoptosis. ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) are the two major DNA damage checkpoint protein kinases which play critical roles in DDR by signaling DNA damage, activating checkpoints, arresting cell cycle progression and facilitating DNA repair to restore DNA integrity. Both ATM and ATR are protein kinases belonging to the phosphoinositide 3-kinase-related protein kinases (PIKK) family and are sensors of cellular stress. Intriguingly, however, a body of evidence from mouse model and human epidemiologic studies show that unlike ATM whose deficiency promotes carcinogenesis, ATR inhibition suppresses carcinogenesis. This is puzzling given the general cancer-suppression role of DNA damage checkpoints. In this project, we will test the hypothesis that (1) besides functioning as a tumor suppressor via its checkpoint regulatory role in the nucleus against moderate DNA damage, ATR in the cytoplasm can function as an anti-apoptotic protein at mitochondria upon severe DNA damage; (2) this anti-apoptotic activity in the cytoplasm occurs via direct involvement of ATR in regulating the DNA damage-induced mitochondria cell death pathways in a checkpoint-independent manner; and (3) this transformation of ATR from tumor suppressor to anti-apoptotic protein is regulated by a prolyl isomeric modification of the cytoplasmic ATR. The modification changes the conformation of ATR, making it anti-apoptotic so that its inhibition suppresses carcinogenesis. These hypotheses will be tested in the following specific aims. Aim 1: To define the UV-induced modification of cytoplasmic ATR and its cellular effects; Aim 2: To determine the mechanisms by which the functions of cytoplasmic ATR are regulated; and Aim 3: To determine the molecular basis of the ATR anti-apoptotic activity at mitochondria. The proposed studies represent an innovative effort highly relevant to cancer and other human diseases such as neurodegenerative and cardiovascular diseases.

描述（由申请人提供）：由于自愿或非自愿暴露于各种环境遗传毒性物质（例如辐射和化学致癌物）而导致的DNA损伤是人类癌症和许多其他人类疾病的主要原因。细胞对DNA损伤的反应是激活几种主要的DNA损伤反应（DDR）途径，如DNA损伤检查点、DNA修复和细胞凋亡。ATM（ataxia telangiectasia mutated）和ATR（ATM and Rad 3-related）是两种主要的DNA损伤检查点蛋白激酶，它们通过发出DNA损伤信号、激活检查点、阻止细胞周期进程和促进DNA修复以恢复DNA完整性而在DDR中发挥关键作用。ATM和ATR都是属于磷酸肌醇3-激酶相关蛋白激酶（PIKK）家族的蛋白激酶，并且是细胞应激的传感器。然而，有趣的是，来自小鼠模型和人类流行病学研究的大量证据表明，与ATM缺陷促进致癌不同，ATR抑制抑制致癌。考虑到DNA损伤检查点的一般癌症抑制作用，这是令人困惑的。在本项目中，我们将验证以下假设：（1）ATR除了通过其在细胞核中的检查点调节作用对中度DNA损伤起肿瘤抑制作用外，在细胞质中还可以在严重DNA损伤时在线粒体中起抗凋亡蛋白的作用;（2）细胞质中的这种抗凋亡活性通过ATR直接参与调节DNA损伤而发生-以检查点非依赖性方式诱导线粒体细胞死亡途径;和（3）ATR从肿瘤抑制因子到抗凋亡蛋白的这种转化受胞质ATR的脯氨酰异构体修饰的调节。这种修饰改变了ATR的构象，使其具有抗凋亡作用，从而抑制了癌的发生。这些假设将在以下具体目标中得到检验。目标1：目的2：确定细胞质ATR功能调节的机制;目的3：确定线粒体ATR抗凋亡活性的分子基础。拟议的研究代表了与癌症和其他人类疾病（如神经退行性疾病和心血管疾病）高度相关的创新努力。