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.

我们发现了一种进化上保守的新突变机制，可导致 FGF 受体 (FGFR) 在细胞表面过度积累。这种现象在果蝇突变体和 恶性肾细胞癌（RCC）培养物。可能的原因是 von Hippel-Lindau 基因突变 肿瘤抑制基因（VHL）。还注意到过度积累的 F​​GFR 会导致异常细胞 Etsl 活性的迁移和诱导。根据这些和其他初步数据，提出一个假设 将研究 FGFR 积累表型背后的新型细胞内机制以及如何 这种异常信号事件通过 Etsl 可以调节细胞运动。我们怀疑该途径至少部分地 通过影响整合素活性来提高细胞运动性。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机制。目标1将 剖析导致 FGFR 过度积累的囊泡转运途径以及失调的影响 信号事件。目标 2 将分析 Etsl 在调节整合素活性中的作用及其相关性 潜在的靶基因Skap55 和整合素|34。目标 3 将检查体内功能关系 使用果蝇和 Etsl 敲除小鼠原代细胞作为模型，研究 Etsl 和整合素之间的关系。最后， 本研究中确定的重要标记基因将在人类肿瘤样本中得到验证。