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: 9975171
• 负责人: MICHAEL B YAFFE
• 金额: $ 54.05万
• 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/9975171
• 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; Epithelium; 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如何 途径与磷酸盐/苏氨酸结合结构域和RNA结合蛋白（RNA- BPS）暴露于炎症和遗传毒性应激后调节肿瘤的发展。我们特别是 有兴趣了解如何操纵这些途径以增强癌症的预防以及 改善对常规抗癌剂形成的任何肿瘤的反应。除了两个 细胞用来响应DNA损伤的规范DNA损伤响应途径，ATR-CHK1途径， 和ATM-CHK2途径，我们最近确定了由 P38MAPK和MAPKAP激酶-2（MK2）对于p53缺陷肿瘤细胞绝对必要 遗传毒性应激之后。重要的是，MK2途径在完整p53功能的细胞中是可分配的，使其成为 特别损害经历癌症转化的细胞能力生存的能力的理想目标 额外的DNA损伤。与专门用于响应的ATR-CHK1和ATM-CHK2途径不同 p38 MAPK-MK2途径仅来自DNA损伤的信号，是一种全球应力响应途径 通过多种类型的细胞应激激活，在炎症过程中在细胞因子产生中起关键作用 和早期肿瘤发育。因此，我们认为p38MAPK-MK2途径起着特别新颖的作用 在遗传毒性应激之后发生的肿瘤发生过程中，通过整合DNA损伤反应途径 在相邻基质微环境中引起的炎症和细胞因子信号传导受损的细胞受损。 重要的是，DNA损伤响应函数和MK2的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-BPS的作用，该作用在转录后水平控制基因表达。最后，我们和其他人有 观察到某些异生元似乎不是通过DNA损伤导致细胞损伤，而是导致死亡 通过明显的RNA损伤响应，迄今为止的特征非常差。 在此提案中，我们（1）研究MK2信号在上皮室和 遗传毒性应激诱导癌症发展的鼠模型中的炎症微环境； （2） 阐明RNA结合蛋白的新兴作用是细胞对DNA的关键介体 损害; （3）探索鲜为人知的RNA损伤响应，诱导了一个深刻的凋亡 各种各样的上皮组织。 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的问题。结果 然后，使用环境压力诱导的癌症和 通过查询人类患者得出的数据集，以实现对环境的变革影响 健康科学。