Protein Kinase Signaling and Cell Cycle Control

描述（由申请人提供）：我们实验室的长期目标是了解，在分子细节上，蛋白激酶信号通路如何与磷酸丝氨酸/苏氨酸结合域一起调节细胞增殖的多个方面，包括细胞周期进程和细胞对DNA损伤的反应。在本文中，我们探讨了MAPKAP激酶-2的功能，这是一种由p38 MAPK激活的应激反应蛋白激酶，在响应环境和内源性DNA损伤时，作为s期和有丝分裂进程的关键调节剂。我们结合广泛的生物化学和分子细胞生物学来探索化学物质和UV-C照射诱导DNA损伤后MAPKAP激酶-2激活的信号转导机制，并研究MAPKAP激酶-2如何与其他检查点激酶（如Chk1）一起在培养细胞中控制基因毒性应激后的细胞周期进程。我们继续开发条件MAPKAP激酶2敲除小鼠，以探索MAPKAP激酶2是否在肉瘤和肺癌的遗传定义模型中作为肿瘤抑制因子，以及在环境致癌物诱导的结直肠癌和皮肤癌模型中发挥作用。最后，我们探讨MAPKAP激酶-2的下调是否促进化学诱导的DNA损伤（如化疗）后的细胞死亡。这些研究应该阐明来自p38 MAPK-MAPKAP激酶-2通路的信号是如何调节细胞对基因毒性应激的反应的，p38 MAPK-MAPKAP激酶-2通路是一个由各种毒性损伤激活的全球应激反应网络，与专用DNA损伤反应通路的信号相结合。这些实验的结果将揭示MAPKAP激酶-2是否作为肿瘤抑制基因，在暴露于环境因子后调节癌症的风险，以及特异性靶向MAPKAP激酶-2是否具有使肿瘤对常规化疗的细胞毒性作用增敏的治疗价值。

DESCRIPTION (provided by applicant): The long-term goal of our laboratory is to understand, in molecular detail, how protein kinase signaling pathways together with phosphoserine/threonine-binding domains regulate multiple aspects of cell proliferation, including cell cycle progression and the cellular response to DNA damage. In the present proposal, we explore the function of MAPKAP Kinase-2, a stress-responsive protein kinase activated by p38 MAPK, as a critical regulator of S-phase and mitotic progression in response to environmental and endogenous types of DNA damage. We use a combination of extensive biochemistry and molecular cell biology to explore the signal transduction mechanisms involved in MAPKAP Kinase-2 activation after DNA damage induced by chemicals and UV-C irradiation, and examine how MAPKAP Kinase-2 functions together with other checkpoint kinases such as Chk1, to control cell cycle progression after genotoxic stress in cells in culture. We go on to develop a conditional MAPKAP Kinase-2 knock-out mouse to explore whether MAPKAP Kinase-2 functions as a tumor suppressor in genetically defined models of sarcoma and lung cancer, and in environmental carcinogen-induced models of colorectal and skin cancer. Finally, we explore whether down-regulation of MAPKAP Kinase-2 facilitates cell death after intentional chemically-induced DNA damage such as chemotherapy. These studies should clarify how signals from the p38 MAPK-MAPKAP Kinase-2 pathway, a global stress-responsive network that is activated by a wide variety of toxic insults, integrate with those from dedicated DNA damage response pathways, to regulate the cellular response to genotoxic stress. The results of the proposed experiments should reveal whether MAPKAP Kinase-2 functions as a tumor suppressor gene that modulates the risk of cancer after exposure to environmental agents, and whether specific targeting of MAPKAP Kinase-2 would be of therapeutic value for sensitizing tumors to the cytotoxic effects of conventional chemotherapy.