Ets1 and FGFR FUNCTIONS IN EPITHELIAL CELL MIGRATION

Ets1 和 FGFR 在上皮细胞迁移中的功能

• 批准号: 6949483
• 负责人: TIEN HSU
• 金额: $ 11.8万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6949483
• 关键词: Drosophilidae; biological signal transduction; cell migration; epithelium; fibroblast growth factor; genetically modified animals; growth factor receptors; integrins; laboratory mouse; metastasis; neoplasm /cancer genetics; transcription factor

We have identified an evolutionarily conserved novel mutational mechanism that leads to FGF receptor (FGFR) over-accumulates on the cell surface. This phenomenon is observed in the Drosophila mutant and in the malignant renal cell carcinoma (RCC) culture. The likely cause is the mutation in the von Hippel-Lindau tumor suppressor gene (VHL). It was also noted that the over-accumulated FGFR leads to aberrant cell migration and induction of Etsl activity. Based on these and other preliminary data, a hypothesis is proposed that will study the novel intracellular mechanism that underlies the FGFR accumulation phenotype and how this aberrant signaling event, via Etsl, can modulate cell motility. We suspect that the pathway at least in part confers elevated cell motility by affecting integrin activities. We will utilize in vitro and in vivo model systems and employ cross-species comparative studies to dissect the signaling mechanisms. Aim 1 will dissect the vesicle transport pathway that results in FGFR over-accumulation and the effects of dysregulated signaling events. Aim 2 will analyze the role of Etsl in modulating the integrin activities, in relation to its potential target genes Skap55 and integrin |34. Aim 3 will examine the in vivo functional relationship between Etsl and integrins using Drosophila and Etsl knockout mouse primary cells as models. Finally, the important marker genes identified in this study will be verified in human tumor samples.

我们已经确定了一种进化保守的新型突变机制，该机制导致FGF受体 （FGFR）在细胞表面过度累积。在果蝇突变体中观察到了这种现象 恶性肾细胞癌（RCC）培养。可能的原因是von Hippel-Lindau中的突变 肿瘤抑制基因（VHL）。还注意到，过度耗尽的FGFR导致异常细胞 ETSL活性的迁移和诱导。基于这些和其他初步数据，提出了一个假设 这将研究基于FGFR积累表型的新型细胞内机制以及如何 通过ETSL，此异常信号事件可以调节细胞运动。我们怀疑这条路至少部分部分 通过影响整联蛋白活性来赋予细胞运动升高。我们将利用体外和体内模型 系统并采用跨物种比较研究来剖析信号传导机制。目标1意志 剖析导致FGFR过度蓄积的囊泡传输途径以及失调的影响 信号事件。 AIM 2将分析ETSL在调节整联蛋白活动中的作用 潜在靶基因SKAP55和整联蛋白| 34。 AIM 3将检查体内功能关系 使用果蝇和ETSL基因敲除小鼠主细胞作为模型，在ETSL和整联蛋白之间。最后， 这项研究中确定的重要标记基因将在人类肿瘤样品中进行验证。