Protein Kinase Signaling and Cell Cycle Control

蛋白激酶信号传导和细胞周期控制

• 批准号: 7535528
• 负责人: MICHAEL B YAFFE
• 金额: $ 35.27万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535528
• 关键词: Apoptosis; Arsenic; Binding; Biochemistry; Cell Aging; Cell Cycle; Cell Cycle Arrest; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Cycle Regulation; Cell Death; Cell Proliferation; Cell division; Cell physiology; Cells; Cellular Stress; Cellular biology; Chemicals; Cisplatin; Colorectal; Colorectal Cancer; Complex; DNA; DNA Damage; DNA strand break; Development; Down-Regulation; Environmental Carcinogens; Exposure to; Gene Targeting; Genes; Genetic; Genotoxic Stress; Goals; Heat-Shock Response; Human; Incidence; Knockout Mice; Laboratories; Lesion; Link; Lung Neoplasms; MAP-kinase-activated kinase 2; MAPK14 gene; MAPKAP kinase-2; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Mitotic; Modeling; Molecular; Mus; Pathway interactions; Phase; Phosphoserine; Phosphotransferases; Protein Kinase; Proteins; RNA Interference; Radiation; Reaction; Recruitment Activity; Research Personnel; Risk; Signal Pathway; Signal Transduction; Skin Cancer; Stress; Technology; Testing; Therapeutic; Threonine; Topoisomerase Inhibitors; Toxin; Treatment Protocols; Tumor Suppressor Genes; Tumor Suppressor Proteins; UV induced DNA damage; Ultraviolet Rays; Virulence; Xenobiotic Metabolism; biological adaptation to stress; cancer risk; chemical carcinogen; chemotherapy; crosslink; cytotoxic; environmental agent; environmental mutagens; improved; irradiation; lung Carcinoma; mitogen-activated protein kinase p38; mutant; programs; repaired; research study; response; sarcoma; sensor; therapy development; tumor; upstream kinase

The long-term goal of our laboratory is to understand, in molecular detail, how protein kinase signaling pathways together with phosphoserine/threonine-binding domains regulate multiple aspects of cell proliferation, including cell cycle progression and the cellular response to DMAdamage. In the present proposal, we explore the function of MAPKAP Kinase-2, a stress-responsive protein kinase activated by p38 MARK, as a critical regulator of S-phase and mitotic progression in response to environmental and endogenous types of DMA damage. We use a combination of extensive biochemistry and molecular cell biology to explore the signal transduction mechanisms involved in MAPKAP Kinase-2 activation after DMA damage induced by chemicals and UV-C irradiation, and examine how MAPKAP Kinase-2 functions together with other checkpoint kinases such as Chk1, to control cell cycle progression after genotoxic stress in cells in culture. We go on to develop a conditional MAPKAP Kinase-2 knock-out mouse to explore whether MAPKAP Kinase-2 functions as a tumor suppressor in genetically defined models of sarcoma and lung cancer, and in environmental carcinogen-induced models of colorectal and skin cancer. Finally, we explore whether down-regulation of MAPKAP Kinase-2 facilitates cell death after intentional chemically-induced DNA damage such as chemotherapy. These studies should clarify how signals from the p38 MAPK-MAPKAP Kinase-2 pathway, a global stress- responsive network that is activated by a wide variety of toxic insults, integrate with those from dedicated DNA damage response pathways,to regulate the cellular response to genotoxic stress. The results of the proposed experiments should reveal whether MAPKAP Kinase-2 functions as a tumor suppressor gene that modulates the risk of cancer after exposure to environmental agents, and whether specific targeting of MAPKAP Kinase-2 would be of therapeutic value for sensitizing tumors to the cytotoxic effects of conventional chemotherapy.

我们实验室的长期目标是从分子细节上了解蛋白激酶信号传导如何 途径与磷酸丝氨酸/苏氨酸结合域一起调节细胞的多个方面 增殖，包括细胞周期进展和细胞对 DMA 损伤的反应。在现在 根据提案，我们探索了 MAPKAP 激酶-2（一种由 p38 激活的应激反应蛋白激酶）的功能 MARK，作为 S 期和有丝分裂进展的关键调节因子，响应环境和 内源性 DMA 损伤。我们结合广泛的生物化学和分子细胞 生物学探索 DMA 后 MAPKAP 激酶 2 激活涉及的信号转导机制 化学物质和 UV-C 照射引起的损伤，并检查 MAPKAP Kinase-2 如何共同发挥作用 与其他检查点激酶（例如 Chk1）一起控制细胞中基因毒性应激后的细胞周期进程 文化。我们继续开发条件性 MAPKAP 激酶 2 敲除小鼠来探索是否 MAPKAP 激酶-2 在基因定义的肉瘤和肺模型中充当肿瘤抑制因子 癌症，以及环境致癌物诱发的结直肠癌和皮肤癌模型。最后，我们探索 有意化学诱导 DNA 后，MAPKAP 激酶 2 的下调是否会促进细胞死亡 化疗等损伤。 这些研究应该阐明来自 p38 MAPK-MAPKAP 激酶 2 通路（一种全局应激通路）的信号是如何产生的。 由各种有毒侮辱激活的响应网络，与来自专用网络的网络集成 DNA损伤反应途径，调节细胞对基因毒性应激的反应。结果 拟议的实验应该揭示 MAPKAP 激酶 2 是否具有肿瘤抑制基因的功能 调节暴露于环境因素后患癌症的风险，以及是否特定针对 MAPKAP 激酶-2 对于使肿瘤对细胞毒性作用敏感具有治疗价值 常规化疗。