Function and Regulation Mechanisms of Polo-like Kinase 3 in Pancreatic Cancer

项目摘要 胰腺癌是癌症研究中最大的挑战之一。胰腺 腺癌是美国成人癌症死亡率的第四大原因。的 5年生存率保持在1- 3%，诊断后的中位生存时间更短 超过六个月胰腺癌的特点是局部晚期或转移性疾病 对目前的治疗缺乏反应。根据最常检测到的突变， 这种疾病，胰腺癌的基因图谱正在出现。马球式的表达 激酶3（Plk 3），四种哺乳动物polo样激酶之一，在近10年内显著降低， 70%的人胰腺癌组织和大多数胰腺癌细胞系中。此外，委员会认为， plk 3定位于染色体1 p32，一个被认为含有癌症易感基因的位点。 最近，产生Plk 3敲除小鼠，并且这些小鼠在各种肿瘤中发展肿瘤。 器官在高龄。Plk 3是一种多功能蛋白，在细胞凋亡中起着关键作用。 调节细胞凋亡和对DNA损伤的反应。Plk 3的表达诱导细胞凋亡 在细胞培养的胰腺癌细胞中， 在异种移植小鼠模型中介导的基因转移。这些发现表明Plk 3 作为肿瘤抑制因子发挥作用，在胰腺癌细胞凋亡中起重要作用。 然而，Plk 3通过其调节的潜在分子机制仍然难以捉摸。 我们研究的长期目标是为患有 胰腺癌根据我们的初步结果，我们假设Plk 3的缺失 Plk 3表达在胰腺癌的发展中起着重要作用， 激活是整合控制基因组不稳定性的信号的重要调节 通过可诱导的磷酸化和/或与接头分子的相互作用。来测试我们 假设，提出了三个具体目标：（1）证明Plk 3在 胰腺癌的发生发展;（2）确定Plk 3在胰腺癌中的表达是否沉默 癌症和Plk 3在控制细胞分裂和DNA损伤检查点中的作用;（3）鉴定 Plk 3的激活机制。我们的研究发现 将提供深入了解Plk 3调节机制和Plk 3作为一种免疫调节剂的重要作用。 胰腺癌的肿瘤抑制因子。重要的是，这项研究可能会发现新的分子 这些目标可能会导致更有效的胰腺癌治疗。

Project Summary Pancreatic cancer poses one of the greatest challenges in cancer research. Pancreatic adenocarcinoma is the fourth-leading cause of adult cancer mortality in the United States. The five-year survival rate remains at 1-3%, and the median survival duration after diagnosis is less than six months. Pancreatic cancer is characterized by locally advanced or metastatic disease and lack of response to current therapies. Based on the most frequently detected mutations in this disease, a genetic profile for pancreatic cancer is emerging. The expression of polo-like kinase 3 (Plk3), one of the four mammalian polo-like kinases, is significantly decreased in nearly 70% of human pancreatic cancer tissues and in most pancreatic cancer cell lines. Furthermore, Plk3 localizes to chromosome 1p32, a locus thought to contain cancer susceptibility genes. Recently, Plk3-knockout mice were generated and these mice developed tumors in various organs at advanced age. Plk3 is a multi-functional protein that plays critical roles in the regulation of apoptosis and responses to DNA damage. Expression of Plk3 induced apoptosis in pancreatic cancer cells in cell culture and inhibited pancreatic tumor growth by liposome- mediated gene transfer in a xenograft mouse model. These findings demonstrate that Plk3 functions as a tumor suppressor and plays an essential role in pancreatic cancer cell apoptosis. However, the underlying molecular mechanism through which Plk3 is regulated remains elusive. The long-term goal of our research is to develop more effective therapies for patients with pancreatic cancer. On the basis of our preliminary results, we hypothesize that loss of Plk3 expression plays an essential role in the development of pancreatic cancer and that Plk3 activation is an essential regulation that integrates signals that control genomic instability through inducible phosphorylation and/or interaction with adaptor molecules. To test our hypotheses, three specific aims were proposed: (1) demonstrate the role of Plk3 in the development of pancreatic cancer; (2) determine the expression of Plk3 is silenced in pancreatic cancer and role of Plk3 in the control of cell division and DNA damage checkpoints; (3) identify the mechanisms by which activation of Plk3 is regulated. The findings from our proposed study will provide insight into the mechanisms of Plk3 regulation and the essential role of Plk3 as a tumor suppressor in pancreatic cancer. Importantly, this study may discover novel molecular targets that could lead to more effective treatments for pancreatic cancer.