Function and Regulation Mechanisms of Polo-like Kinase 3 in Pancreatic Cancer
Polo样激酶3在胰腺癌中的功能及调控机制
基本信息
- 批准号:8029562
- 负责人:
- 金额:$ 31.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-04-01 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:1p32AdultApoptosisArchitectureArginineBindingBiochemicalBiologicalC-terminalCancer cell lineCancer-Predisposing GeneCell Culture TechniquesCell CycleCell Cycle RegulationCell LineCell divisionCellsChromosomesCleaved cellCytokine-Inducible KinaseDNA DamageDNA damage checkpointDataDevelopmentDiagnosisDiseaseDown-RegulationDuctalElderlyEndopeptidasesEpithelialFoundationsG2/M ArrestGenomic InstabilityGoalsHumanIn VitroKnockout MiceLeadLeftLigandsLiposome-Mediated Gene TransferMalignant NeoplasmsMalignant neoplasm of pancreasMammalian CellMediatingMitosisMitoticModelingMolecularMolecular TargetMusMutant Strains MiceMutateMutationNormal tissue morphologyNucleic Acid Regulatory SequencesOrganPancreasPancreatic AdenocarcinomaPatientsPhosphatidylinositolsPhosphorylationPhosphotransferasesPhysiologicalPlayPolo-Box DomainProtein-Serine-Threonine KinasesProteinsRegulationResearchResearch PersonnelResistanceRoleS PhaseSignal PathwaySignal TransductionSiteSurvival RateTestingTissuesTumor Suppressor ProteinsUnited StatesWorkXenograft procedureanticancer researchbasecancer cellcancer typeeffective therapygenetic profilinghuman PLK1 proteinimprovedin vivoinsightmortalitymouse modelmutantnoveloverexpressionpancreatic cancer cellspancreatic neoplasmphosphatidylinositol 3,4,5-triphosphatepublic health relevanceresearch studyresponsetripolyphosphatetumortumor growthtumorigenesis
项目摘要
DESCRIPTION (provided by applicant): 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.
PUBLIC HEALTH RELEVANCE: This project is aimed at elucidating the tumor suppressor function of Plk3 in pancreatic tumor development and determining the novel mechanism by which Plk3 is silenced and regulated. We hypothesize that down regulation of Plk3 plays an essential role in development of pancreatic cancer and activation of Plk3 by proteolytic cleavage is regulated by PI3K. We will test our hypothesis by three specific aims using a combination of Plk3 knockout mouse models and Plk3 knockdown cell lines with biochemical and cell biological approaches, to fill in the gaps in our understanding of the novel molecular mechanisms of Plk3 regulation and role of Plk3 in tumorigenesis of pancreas.
描述(由申请人提供):胰腺癌是癌症研究中最大的挑战之一。胰腺癌是美国成人癌症死亡率的第四大原因。五年生存率维持在1-3%,诊断后中位生存期不到六个月。胰腺癌的特点是局部晚期或转移性疾病,并且对当前疗法缺乏反应。根据这种疾病中最常检测到的突变,胰腺癌的遗传图谱正在出现。 Polo 样激酶 3 (Plk3) 是四种哺乳动物 Polo 样激酶之一,其表达在近 70% 的人类胰腺癌组织和大多数胰腺癌细胞系中显着降低。此外,Plk3 定位于染色体 1p32,该基因座被认为含有癌症易感基因。最近,产生了 Plk3 敲除小鼠,这些小鼠在高龄时各个器官出现肿瘤。 Plk3 是一种多功能蛋白,在细胞凋亡的调节和 DNA 损伤反应中发挥着关键作用。在异种移植小鼠模型中,Plk3 的表达诱导细胞培养中的胰腺癌细胞凋亡,并通过脂质体介导的基因转移抑制胰腺肿瘤的生长。这些发现表明 Plk3 作为肿瘤抑制因子发挥作用,并在胰腺癌细胞凋亡中发挥重要作用。然而,调节 Plk3 的潜在分子机制仍然难以捉摸。我们研究的长期目标是为胰腺癌患者开发更有效的疗法。根据我们的初步结果,我们假设 Plk3 表达缺失在胰腺癌的发展中起着至关重要的作用,并且 Plk3 激活是一种重要的调节,通过诱导磷酸化和/或与接头分子相互作用来整合控制基因组不稳定性的信号。为了检验我们的假设,提出了三个具体目标:(1)证明Plk3在胰腺癌发生中的作用; (2)确定Plk3在胰腺癌中的表达被沉默以及Plk3在控制细胞分裂和DNA损伤检查点中的作用; (3)确定Plk3激活的调节机制。我们提出的研究结果将深入了解 Plk3 调节机制以及 Plk3 作为胰腺癌肿瘤抑制因子的重要作用。重要的是,这项研究可能会发现新的分子靶点,从而为胰腺癌提供更有效的治疗方法。
公共健康相关性:该项目旨在阐明 Plk3 在胰腺肿瘤发展中的肿瘤抑制功能,并确定 Plk3 被沉默和调节的新机制。我们假设 Plk3 的下调在胰腺癌的发展中起着重要作用,并且通过蛋白水解裂解激活 Plk3 受到 PI3K 的调节。我们将使用 Plk3 敲除小鼠模型和 Plk3 敲除细胞系与生化和细胞生物学方法相结合,通过三个具体目标来检验我们的假设,以填补我们对 Plk3 调控的新分子机制和 Plk3 在细胞中的作用的理解上的空白。胰腺肿瘤发生。
项目成果
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{{ truncateString('PAUL J CHIAO', 18)}}的其他基金
Mechanisms of Overexpressed TrkB in Inducing Pancreatic Cancer Metastasis
过表达TrkB诱导胰腺癌转移的机制
- 批准号:
8105209 - 财政年份:2010
- 资助金额:
$ 31.8万 - 项目类别:
Function and Regulation Mechanisms of Polo-like Kinase 3 in Pancreatic Cancer
Polo样激酶3在胰腺癌中的功能及调控机制
- 批准号:
8445298 - 财政年份:2010
- 资助金额:
$ 31.8万 - 项目类别:
Mechanisms of Overexpressed TrkB in Inducing Pancreatic Cancer Metastasis
过表达TrkB诱导胰腺癌转移的机制
- 批准号:
8464658 - 财政年份:2010
- 资助金额:
$ 31.8万 - 项目类别:
Function and Regulation Mechanisms of Polo-like Kinase 3 in Pancreatic Cancer
Polo样激酶3在胰腺癌中的功能及调控机制
- 批准号:
8637001 - 财政年份:2010
- 资助金额:
$ 31.8万 - 项目类别:
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- 批准号:
7987576 - 财政年份:2010
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$ 31.8万 - 项目类别:
Function and Regulation Mechanisms of Polo-like Kinase 3 in Pancreatic Cancer
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7888882 - 财政年份:2010
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$ 31.8万 - 项目类别:
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