Protein Kinase Signaling in the Genotoxic Stress Response

基因毒性应激反应中的蛋白激酶信号转导

• 批准号: 10219250
• 负责人: MICHAEL B YAFFE
• 金额: $ 53.21万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10219250
• 关键词: Antineoplastic Agents; Apoptosis; Binding; Cell Death; Cells; Cellular Stress; Cytokine Signaling; DNA Damage; Data Set; Development; Environmental Exposure; Environmental Health; Epithelial; Epithelial Cells; Exposure to; Gene Expression; Genetic Transcription; Genotoxic Stress; Goals; Human; Impairment; Incidence; Inflammation; Inflammatory; Laboratories; MAP Kinase Gene; MAPKAPK2 gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Pathway interactions; Patients; Phosphoserine; Play; Production; Protein Kinase; RNA; RNA-Binding Proteins; Role; Signal Pathway; Signal Transduction; Stimulus; Stress; TP53 gene; Threonine; Tissues; Toxin; Xenobiotics; biological adaptation to stress; cancer prevention; cell injury; cytokine; flexibility; improved; in vivo evaluation; interest; mouse model; neoplastic cell; novel; p38 Mitogen Activated Protein Kinase; protein function; response; therapeutic target; tumor; tumorigenesis

Project Summary: The long-term goal of our laboratory is to understand how specific protein kinase signaling pathways function together with phosphoserine/threonine-binding domains and RNA binding proteins (RNA- BPs) to regulate tumor development after exposure to inflammation and genotoxic stress. We are particularly interested in understanding how these pathways can be manipulated to enhance cancer prevention, as well as to improve the response of any tumors that do form to conventional anti-cancer agents. In addition to the two canonical DNA damage response pathways that cells use to respond to DNA damage, the ATR-Chk1 pathway, and the ATM-Chk2 pathway, we recently identified a third DNA damage response pathway mediated by p38MAPK and MAPKAP Kinase-2 (MK2) that is absolutely essential for p53-defective tumor cells to survive after genotoxic stress. Importantly, the MK2 pathway is dispensable in cells with intact p53 function, making it an ideal target for specifically impairing the ability of cells undergoing cancer transformation to survive additional DNA damage. Unlike the ATR-Chk1 and ATM-Chk2 pathways that are dedicated to responding solely to signals from DNA damage, the p38 MAPK-MK2 pathway is a global stress-response pathway activated by multiple types of cellular stress, and plays a critical role in cytokine production during inflammation and early tumor development. Thus, we believe that the p38MAPK-MK2 pathway plays a particularly novel role during oncogenesis following genotoxic stress by integrating DNA damage response pathways within the damaged cells with inflammation and cytokine signaling arising in the adjacent stromal microenvironment. Importantly, both the DNA damage response function, and the cytokine production function of MK2, as well as many of the activities controlled by ATM-Chk2 and ATR-Chk1, appear to be mediated, in large part, by the action of RNA-BPs, which control gene expression at the post-transcriptional level. Finally, we and others have observed that certain xenobiotics appear to cause cell injury and death not through DNA damage, but instead through a distinct RNA damage response that has been very poorly characterized to date. In this proposal we (1) investigate the role of MK2 signaling in both the epithelial compartment and the inflammatory microenvironment in murine models of genotoxic stress-induced cancer development; (2) elucidate the emerging roles of RNA-binding proteins as key mediators of the cellular response to DNA damage; and (3) explore a poorly understood RNA damage response that induces profound apoptosis in a wide variety of epithelial tissues. The flexibility afforded by R-35 mechanism allows us to pursue these questions using a wide variety of combined experimental and computational approaches. The resulting mechanistic models are then tested in vivo using murine models of environmental stress-induced cancer and by querying human patient derived datasets, in order to achieve a transformational impact in the environmental health sciences.

项目摘要：我们实验室的长期目标是了解特定的蛋白激酶信号传导如何 途径与磷酸丝氨酸/苏氨酸结合域和 RNA 结合蛋白 (RNA- BP）在暴露于炎症和基因毒性应激后调节肿瘤的发展。我们特别 有兴趣了解如何操纵这些途径来加强癌症预防，以及 改善任何已形成的肿瘤对传统抗癌药物的反应。除了这两个 细胞用来响应 DNA 损伤的典型 DNA 损伤反应途径，即 ATR-Chk1 途径， 和 ATM-Chk2 途径，我们最近发现了第三种 DNA 损伤反应途径 p38MAPK 和 MAPKAP 激酶 2 (MK2) 对于 p53 缺陷型肿瘤细胞的生存至关重要 遗传毒性应激后。重要的是，MK2 通路在具有完整 p53 功能的细胞中是可有可无的，这使得 专门损害正在经历癌症转化的细胞生存能力的理想靶点 额外的 DNA 损伤。与专门响应的 ATR-Chk1 和 ATM-Chk2 通路不同 p38 MAPK-MK2 通路仅针对来自 DNA 损伤的信号，是一条全局应激反应通​​路 被多种类型的细胞应激激活，并在炎症过程中细胞因子的产生中发挥关键作用 和早期肿瘤发展。因此，我们相信 p38MAPK-MK2 通路发挥着特别新颖的作用 在基因毒性应激后的肿瘤发生过程中，通过整合 DNA 损伤反应途径 邻近基质微环境中产生炎症和细胞因子信号传导的受损细胞。 重要的是，MK2 的 DNA 损伤反应功能和细胞因子产生功能，以及 许多由 ATM-Chk2 和 ATR-Chk1 控制的活动似乎在很大程度上是由 RNA-BP 的作用，在转录后水平控制基因表达。最后，我们和其他人 观察到某些外源物质似乎不是通过 DNA 损伤引起细胞损伤和死亡，而是通过 通过一种独特的 RNA 损伤反应，迄今为止，这种反应的特征还很不清楚。 在本提案中，我们 (1) 研究 MK2 信号传导在上皮区室和 基因毒性应激诱导癌症发展的小鼠模型中的炎症微环境； (2) 阐明 RNA 结合蛋白作为细胞对 DNA 反应的关键介质的新作用 损害; (3) 探索一种鲜为人知的 RNA 损伤反应，该反应在细胞中诱导深度细胞凋亡 上皮组织种类繁多。 R-35 机制提供的灵活性使我们能够追求这些 使用各种组合的实验和计算方法来提出问题。由此产生的 然后使用环境应激诱发癌症的小鼠模型在体内测试机制模型 通过查询人类患者衍生的数据集，以实现对环境的变革性影响 健康科学。