Checkpoint Kinase Chk1 in Cancer Biology and Therapy

检查点激酶 Chk1 在癌症生物学和治疗中的应用

基本信息

批准号：
7558529
负责人：
TONY R. HUNTER
金额：
$ 36.39万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-03 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7558529
关键词：
ATM activation ATR protein kinase Alkylating Agents Antineoplastic Agents Apoptosis Area Ataxia-Telangiectasia-Mutated protein kinase Attention Biochemical Biological Camptothecin Cancer Biology Cancer Etiology Cancer Patient Cancer cell line Cell Cycle Cell Cycle Arrest Cell Cycle Checkpoint Cell Death Cell Nucleus Cell Respiration Cell Survival Cell division Cells Checkpoint kinase 1 Chromosome Segregation Chromosomes Clinic Clinical Collaborations Complement Complex DNA DNA Damage DNA Double Strand Break DNA Repair Pathway DNA biosynthesis DNA replication fork Data Defect Degradation Pathway Down-Regulation Environment Enzymes Eukaryotic Cell Event Evolution F-Box Proteins Failure Fission Yeast Genetic Genetic Recombination Genome Genotoxic Stress Growth Human Hypoxia Insulin-Like-Growth Factor I Receptor Investigation Ionizing radiation Laboratories Lead Lesion Ligase Maintenance Malignant Neoplasms Mammalian Cell Mediating Metabolic stress Metabolism Mitotic Checkpoint Mitotic Chromosome Molecular Monitor Mothers Movement Mutagens Nature Null Lymphocytes Outcome Paper Pathway interactions Pharmaceutical Preparations Phase Phosphorylation Phosphotransferases Predisposition Principal Investigator Protein Phosphatase 2A Regulatory Subunit PR53 Proteins Publishing Radio Recovery Regulation Replication-Associated Process Research Research Personnel Resistance Resistance development Role Signal Transduction Site Stress System Therapeutic Therapeutic Agents Therapeutic Index Topoisomerase Inhibitors Ubiquitin Ubiquitination Work Xenopus activator of DNA replication assault base biological adaptation to stress cancer cell cell killing cytotoxic cytotoxicity daughter cell drug discovery egg experience helicase histone modification human FRAP1 protein insight intein interest multicatalytic endopeptidase complex neoplastic cell novel prevent programs repaired response ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Project Summary: Eukaryotic cells have elaborate genome surveillance and repair machinery that insures accurate and timely execution of cell-cycle events, such as DNA replication. Defects in this machinery lead to genetic instability and increased cancer susceptibility. Replication stress is induced by damaged DNA, which stalls movement of DNA replication forks. This activates the 'replication checkpoint' to transmit signals that delay S-phase progression, and stabilize stalled forks so that DNA replication can resume after repair of the initiating lesion. The protein kinases, ATR and its downstream target, Chk1 are key components in this pathway. Loss of ATR or Chk1 function is lethal in both normal and malignant cells, underscoring the importance of the replication checkpoint in maintaining genome integrity. Several clinically useful anticancer agents (e.g. camptothecins (CRTs), target DNA replication, and are activators of the replication checkpoint. Preliminary studies of CPT-induced cytotoxicity in cancer cells led to the unexpected discovery that drug-treated cells had reduced Chk1 protein. Other agents (e.g., deep hypoxia, MMS or ionizing radiation) that cause fork stalling also elicit Chk1 downregulation. Chk1 degradation depends on cullin-containing E3 ubiquitin ligases; Chk1 destruction leads to irreversible replication arrest, DNA damage, and cell death. Defects in Chk1 degradation confer resistance to the cytotoxic effect of CPT - a major problem with this class of drugs in the clinic. This novel Chk1 regulation mechanism has important implications for our understanding of S-phase checkpoint signaling, as well as mechanisms of anticancer resistance in cancer patients. We propose to elucidate the underlying mechanisms and significance of stress-induced Chk1 destruction as follows: (1) Identify components of the E3 ligase complexes responsible for Chk1 destruction in cells exposed to replication stress; (2) Identify the putative 'degron' in Chk1; (3) Characterize mechanisms underlying defects in Chk1 degradation in CPT-resistant cancer cells; (4) Determine if failure to degrade Chk1 increases cancer cell resistance to hypoxia and alters response to chemo/radio-therapeutic agents. Relevance: The results of these studies will not only advance our understanding of the genotoxic stress response machinery in human cells, but also provide important insights into the antitumor mechanism of an important class of anticancer agents.

描述（由申请人提供）：项目摘要：真核细胞具有详尽的基因组监视和修复机制，可确保细胞周期事件的准确和及时执行，例如DNA复制。这种机械的缺陷导致遗传不稳定和癌症敏感性提高。复制应力是由受损的DNA诱导的，DNA损害了DNA复制叉的运动。这激活了“复制检查点”以传输延迟S期进展的信号，并稳定停滞的叉子，以便在修复起始病变后可以恢复DNA复制。蛋白激酶，ATR及其下游靶标CHK1是该途径中的关键成分。在正常和恶性细胞中，ATR或CHK1功能的丧失都是致命的，强调了复制检查点在维持基因组完整性方面的重要性。几种临床上有用的抗癌剂（例如，摄影剂（CRT），靶DNA复制，是复制检查点的激活因子。癌细胞中CPT诱导的细胞毒性的初步研究导致了意外发现的发现，导致药物治疗的细胞导致了其他患者，例如其他患者（例如，散布了CHK1蛋白质）。 CHK1下调。 S期检查点信号传导以及癌症患者的抗癌耐药性机制。（2）确定CHK1中的假定“ Degron”；（3）表征CPT耐药细胞中CHK1降解中缺陷的机制；（4）确定未降解CHK1是否会增加对缺氧的癌细胞耐药性并改变对化学/放射治疗剂的反应。相关性：这些研究的结果不仅会提高我们对人类细胞中遗传毒性应激反应机制的理解，而且还提供了对重要类型抗癌药物的抗肿瘤机制的重要见解。