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.

项目概述：我们实验室的长期目标是了解特定蛋白激酶信号是如何产生的