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

基本信息

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
项目类别：
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

项目摘要

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剂（例如辐射和化学致癌物）引起的DNA损害是人类癌症和许多其他人类疾病的主要原因。为了应对DNA损伤，细胞激活了几种主要的DNA损伤反应（DDR）途径，例如DNA损伤检查点，DNA修复和凋亡。 ATM（temectiocia telangiectia突变）和ATR（与ATM和RAD3相关）是两个主要的DNA损伤检查点蛋白激酶，它们通过信号DNA损伤，激活检查点，阻止细胞周期进展并促进DNA修复以恢复DNA完整性，在DDR中起关键作用。 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的缺乏促进了致癌作用不同，ATR抑制作用抑制了癌变。考虑到DNA损伤检查点的一般癌症抑制作用，这令人困惑。在该项目中，我们将测试以下假设：（1）除了通过其检查点调节作用在核中起作用肿瘤抑制因子，在对中度DNA损伤的核中，在严重DNA损伤下，细胞质中的ATR还可以充当线粒体的抗凋亡蛋白；（2）细胞质中的这种抗凋亡活性是通过直接参与ATR以独立于检查点的方式调节DNA损伤诱导的线粒体细胞死亡途径的。（3）ATR从肿瘤抑制剂到抗凋亡蛋白的转化受细胞质ATR的脯氨酰同构体的调节调节。修饰改变了ATR的构象，使其抗凋亡使其抑制作用抑制了癌变。这些假设将在以下特定目标中进行检验。目标1：定义紫外线诱导的细胞质ATR的修饰及其细胞效应；目标2：确定调节细胞质ATR功能的机制；和目标3：确定线粒体ATR抗凋亡活性的分子基础。提出的研究代表了与癌症和其他人类疾病（例如神经退行性和心血管疾病）高度相关的创新努力。