Protein Kinase Signaling in the Genotoxic Stress Response

项目总结：我们实验室的长期目标是了解特定的蛋白激酶信号如何 通路与磷酸丝氨酸/苏氨酸结合区和RNA结合蛋白(RNA- BPS)，以调节暴露于炎症和遗传毒性应激后的肿瘤发展。我们特别是 有兴趣了解如何操纵这些途径来加强癌症预防，以及 以改善任何对传统抗癌药物形成的肿瘤的反应。除了这两个 细胞用来对DNA损伤做出反应的典型DNA损伤反应通路，ATR-Chk1通路， 和ATM-Chk2途径，我们最近发现了第三个DNA损伤反应途径，通过 P38MAPK和MAPKAP Kinase-2(MK2)是P53缺陷肿瘤细胞存活必不可少的信号通路 在基因毒性应激之后。重要的是，MK2通路在具有完整P53功能的细胞中是不必要的，使其 特异性削弱癌细胞转化细胞存活能力的理想靶点 额外的DNA损伤。与专用于响应的ATR-Chk1和ATM-Chk2通路不同 P38mapk-mk2信号通路是一条全球性的应激反应通路。 由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 和早期肿瘤的发展。因此，我们认为p38MAPK-MK2通路具有特别新的作用 在遗传毒性应激后的肿瘤发生过程中整合DNA损伤反应通路 邻近间质微环境中出现炎症和细胞因子信号的受损细胞。 重要的是，DNA损伤反应功能，以及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，它在转录后水平控制基因的表达。最后，我们和其他人 观察到某些外源物质似乎不是通过DNA损伤而是通过DNA损伤导致细胞损伤和死亡 通过一种截然不同的RNA损伤反应，到目前为止，这种反应的特征非常糟糕。 在这个方案中，我们(1)研究了MK2信号在上皮室和上皮室的作用 基因毒性应激诱发肿瘤小鼠模型中的炎性微环境； 阐明RNA结合蛋白作为细胞对DNA反应的关键介质的新作用 以及(3)探索一种知之甚少的RNA损伤反应，该反应可诱导细胞深刻的凋亡。 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 使用多种实验和计算相结合的方法进行提问。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和 通过查询人类患者派生的数据集，以实现对环境的转型影响 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.