激酶Pak2调控Caspase-3抑制细胞凋亡的机制研究

项目名称： 激酶Pak2调控Caspase-3抑制细胞凋亡的机制研究

项目编号： No.31301144

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 李翔

作者单位： 郑州大学

项目金额： 25万元

中文摘要： Pak2作为Pak家族的一员，在细胞生长，细胞分裂，细胞凋亡以及内分泌激素信号通路中起着重要的作用。研究表明，Pak2在多种肿瘤组织和细胞中特异性地高表达，但是其与肿瘤发生的关系以及诱导肿瘤形成的分子机制仍不清楚。我们前期的研究结果显示，Pak2在食管癌组织中高表达，Pak2可以磷酸化Caspase-3在苏氨酸77,152,245位点，并且抑制Caspase-3的活性，暗示肿瘤细胞可能利用其高表达的Pak2逃逸细胞凋亡的监控，从而促进肿瘤的生长。本项目将以Pak2对Caspase-3的磷酸化为研究基点，通过免疫沉淀，软琼脂集落形成实验，shRNA等方法，进一步深入地研究Pak2在细胞增殖和细胞凋亡中的作用，从而在分子机制上揭示Pak2高表达与肿瘤发生和发展的关系；同时将筛选出特异性Pak2抑制剂，利用细胞和动物模型对以Pak2为靶点的食管癌治疗进行初步的研究，为肿瘤治疗提供新的理论基础。

中文关键词： Pak2；Caspase-3；磷酸化；食管癌；热激

英文摘要： p21-activated protein kinase 2 (Pak2), a member of the PAK family of serine/threonine protein kinases, plays an important role in physiological processes such as cell survival, cell mitosis, and cell apoptosis. Accumulating evidence indicates that Pak2 are highly expressed in a lot of cancer tissues compared with normal tissues. However, the mechanism between Pak2 and tumor formation remains unknown. Here, our research data shows that Pak2 is highly expressed in esophageal carcinoma compared with normal esophageal tissues, and Pak2 can phosphorylate Caspase-3 at Threonine77, 152, 245 sites, the phosphorylation of Caspase-3 decreases its activity, which suggest that highly expressed Pak2 mediates cell apoptosis escape and tumor growth by negatively regulating Caspase-3 activity. To reveal the mechanism of highly expressed Pak2 in tumor initiation and development, we plan to further study the function of Pak2 in cell proliferation, cell transformation and cell apoptosis using immunoprecipitation, soft agar assay, and shRNA based on our present data. At the same time, we will select the specific Pak2 inhibitor, using the cell and animal model to determine its effect in esophageal carcinoma treatment, which will provide the strategy of using Pak2 as a novel target for cancer therapy.

英文关键词： Pak2；Caspase-3；Phosphorylation；esophageal cancer；hot stimulation