Protein Kinase Signaling in the Genotoxic Stress Response

项目概述：我们实验室的长期目标是了解特定的蛋白激酶信号是如何 途径与磷酸丝氨酸/苏氨酸结合结构域和RNA结合蛋白（RNA- BPs）在暴露于炎症和遗传毒性应激后调节肿瘤发展。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 以改善任何肿瘤对常规抗癌剂的反应。除了两 细胞用来响应DNA损伤的典型DNA损伤响应途径，ATR-Chk 1途径， 和ATM-Chk 2途径，我们最近确定了第三种DNA损伤反应途径， p38 MAPK和MAPKAP激酶-2（MK2）对于p53缺陷型肿瘤细胞的存活是绝对必要的 基因毒性应激后重要的是，MK 2通路在具有完整p53功能的细胞中被阻断，使其 一个理想的目标，专门削弱能力的细胞经历癌症转化的生存 额外的DNA损伤与ATR-Chk 1和ATM-Chk 2通路不同， p38 MAPK-MK2通路是一个全局性的应激反应通路，仅与DNA损伤信号相关 由多种类型的细胞应激激活，并在炎症期间的细胞因子产生中起关键作用 和早期肿瘤发展。因此，我们认为p38 MAPK-MK2通路发挥了特别新颖的作用， 在遗传毒性应激后的肿瘤发生过程中， 损伤的细胞伴随邻近基质微环境中产生的炎症和细胞因子信号传导。 重要的是，MK2的DNA损伤应答功能和细胞因子产生功能，以及 ATM-Chk 2和ATR-Chk 1控制的许多活动似乎在很大程度上由 RNA-BP的作用，其在转录后水平控制基因表达。最后，我们和其他人 观察到某些外源性物质似乎不是通过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，这种反应的特征非常差。 在这个提议中，我们（1）研究MK2信号在上皮区室和上皮细胞中的作用。 遗传毒性应激诱导的癌症发展的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 损伤;（3）探索一个知之甚少的RNA损伤反应，诱导细胞凋亡， 各种各样的上皮组织R-35机制提供的灵活性使我们能够实现这些目标， 问题使用各种各样的实验和计算相结合的方法。所得 然后使用环境应激诱导的癌症的鼠模型在体内测试机理模型， 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

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.