Protein Kinase Signaling and Cell Cycle Control

我们实验室的长期目标是从分子层面上了解蛋白激酶信号是如何 途径与磷酸丝氨酸/苏氨酸结合域一起调节细胞的多个方面， 增殖，包括细胞周期进程和细胞对DMADamage的反应。本 因此，本研究拟探讨由p38激活的应激反应蛋白激酶MAPKAP激酶2的功能 MARK作为S期和有丝分裂进程的关键调节因子， 内源性DMA损伤。我们综合运用了广泛的生物化学和分子细胞 生物学，以探索DMA后MAPKAP激酶-2激活的信号转导机制 化学品和UV-C辐射引起的损伤，并研究MAPKAP激酶-2如何共同发挥作用 与其他检查点激酶如Chk 1一起，在细胞中基因毒性应激后控制细胞周期进程， 文化我们继续开发条件性MAPKAP激酶-2敲除小鼠，以探索是否 MAPKAP激酶-2在遗传定义的肉瘤和肺模型中作为肿瘤抑制因子发挥作用 癌症，以及环境致癌物诱导的结肠直肠癌和皮肤癌模型。最后，我们探索 MAPKAP激酶-2的下调是否促进有意化学诱导DNA后的细胞死亡 如化疗等。 这些研究应该阐明来自p38 MAPK-MAPKAP激酶-2通路的信号，一个全球性的应激反应， 一个反应网络，是由各种各样的有毒侮辱激活，与那些从专门的整合 DNA损伤反应途径，调节细胞对遗传毒性应激的反应。的结果 提出的实验应该揭示MAPKAP激酶-2是否作为肿瘤抑制基因发挥作用， 调节暴露于环境因子后的癌症风险，以及是否特异性靶向 MAPKAP激酶-2对于使肿瘤对MAPKAP激酶的细胞毒性作用敏感具有治疗价值。 常规化疗。

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 DMAdamage. In the present proposal, we explore the function of MAPKAP Kinase-2, a stress-responsive protein kinase activated by p38 MARK, as a critical regulator of S-phase and mitotic progression in response to environmental and endogenous types of DMA 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 DMA 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.