The role of RalA in pancreatic tumorigenesis
RalA在胰腺肿瘤发生中的作用
基本信息
- 批准号:8132462
- 负责人:
- 金额:$ 13.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-09-01 至 2013-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAllelesBindingCancer EtiologyCancer cell lineDevelopmentDiseaseGoalsGrowthHumanKRAS2 geneMalignant neoplasm of pancreasMediatingMusMutationOncogenicPancreasPathway interactionsPhosphorylationPhosphotransferasesRegulationResearch PersonnelRoleSerineSignal TransductionTransgenic MiceTreatment ProtocolsUnited Statesaurora-A kinasebasecancer cellimprovedloss of functionmortalitynew therapeutic targetnovel therapeutic interventionnovel therapeuticsoutcome forecastpancreatic cancer cellspancreatic tumorigenesisprogramstreatment strategytumorigenesistumorigenic
项目摘要
DESCRIPTION (provided by applicant): Pancreatic cancer has a dismal prognosis due in large part to the ineffectiveness of current treatment regimens. Our long-term goal is to identify key factors underlying pancreatic cancer development so that they can be targeted for new therapeutic strategies. Our hypothesis is that activation of RalA by both K-Ras and Aurora-A kinase is a key step in pancreatic tumorigenesis. This hypothesis is based on the following: 1) Nearly all pancreatic cancers have an activating mutation in the oncogene K-Ras critical for tumorigenesis, and this oncogenic signal is mediated in large part by the RalGEF pathway in humans; 2) the transforming RalGEF effector RalA is crucial for both transformed and tumorigenic growth of pancreatic cancer cell lines; 3) RalA serine 194, which is phosphorylated by Aurora-A kinase, is required for transformation of RalGEF-dependent human cancer cells; and 4) Aurora-A inhibition decreases tumorigenic growth of pancreatic cancer cell lines. We propose to evaluate the roles of RalA and Aurora-A in pancreatic tumorigenesis.
Specific Aim 1: Determine if loss of RalA inhibits K-ras-driven pancreatic tumorigenesis in mice. We will evaluate spontaneous pancreatic tumorigenesis in transgenic mice which conditionally express an oncogenic K-ras allele but not RalA in the pancreas.
Specific Aim 2: Determine whether RalA functions through its known effectors RalBP1, Exo84, or Sec5 to mediate the development of pancreatic cancer. We will a) perform loss-of-function analysis of the candidate RalA downstream effectors RalBP1, Exo84, or Sec5, and determine the effect on the transformation and tumorigenic growth of pancreatic cancer cell lines, and b) determine whether phosphorylation of RalA S194 alters the binding affinities of RalA for RalBP1, Exo84, or Sec5.
Specific Aim 3: Determine whether Aurora-A phosphorylation of RalA S194 enhances pancreatic cancer growth. We will a) establish whether phosphorylation of RalA S194 by Aurora-A is required for transformed and tumorigenic growth in pancreatic cancer cell lines, b) establish whether Aurora-A inhibition requires RalA S194 to decrease growth of pancreatic cancer cells, and c) determine whether RalA S194 phosphorylation causes intracellular relocalization of RalA in pancreatic cancer cells.
描述(由申请人提供):胰腺癌预后不佳,很大程度上是由于目前治疗方案的无效。我们的长期目标是确定胰腺癌发展的关键因素,以便制定新的治疗策略。我们的假设是K-Ras和Aurora-A激酶对RalA的激活是胰腺肿瘤发生的关键步骤。该假设基于以下内容:1)几乎所有的胰腺癌在癌基因K-Ras中都有一个对肿瘤发生至关重要的激活突变,而这种致癌信号在很大程度上是由人类的RalGEF通路介导的;2)转化性RalGEF效应因子RalA对胰腺癌细胞系的转化性生长和致瘤性生长都至关重要;3) RalA丝氨酸194被Aurora-A激酶磷酸化,是依赖ralgef的人癌细胞转化所必需的;4)抑制Aurora-A可降低胰腺癌细胞系的致瘤性生长。我们建议评估RalA和Aurora-A在胰腺肿瘤发生中的作用。
项目成果
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Stephan DiSean Kendall其他文献
Stephan DiSean Kendall的其他文献
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