FUNCTIONAL ANALYSIS OF NF2 GENE MUTATIONS

NF2基因突变的功能分析

• 批准号: 6319500
• 负责人: David H Gutmann
• 金额: $ 2.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-28 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6319500
• 关键词: RNA splicing; Schwann cells; athymic mouse; biological signal transduction; cell growth regulation; cell line; cell motility; confocal scanning microscopy; flow cytometry; gene expression; gene mutation; intermolecular interaction; neoplastic process; neoplastic transformation; neurofibromatosis; neurogenetics; polymerase chain reaction; protein isoforms; protein structure function; transfection; tumor suppressor proteins; western blottings

DESCRIPTION (From the applicant's abstract): Little is known about the molecular pathogenesis of nervous system tumors such as meningiomas and schwannomas. Individuals affected with neurofibromatosis 2 (NF2) develop these tumors at increased frequency. In addition, mutations and loss of NF2 gene expression are associated with the development of sporadic schwannomas and meningiomas, suggesting that the NF2 gene product, merlin is a critical growth regulator for Schwann cells and meningeal cells. The NF2 tumor suppressor gene bears sequence similarity to Protein4.1 proteins that link the actin cytoskeleton to cell surface glycoproteins. Previous work from out laboratory has demonstrated that merlin regulates cell motility and proliferation as well as cell spreading. In this application we propose to test the hypothesis that merlin integrates several different several cellular processes important for tumor formation and progression reflected by its ability to regulate cell spreading (tumor initiation), cell proliferation (tumor growth) and cell motility (tumor spread). The experiments proposed in this application are aimed at determining how the merlin tumor suppressor functions as a negative growth regulator by defining merlin functional domains, critical merlin protein interactions and relevant intracellular signaling pathways. Our ability to design rational therapies for schwannomas and meningiomas is dependent on an improved understanding of the mechanisms by which loss of merlin expression and function promotes tumor formation.

描述(摘自申请者的摘要)：对 神经系统肿瘤的分子发病机制，如脑膜瘤和 神经鞘瘤。患有神经纤维瘤病2(NF2)的人会患上这些 肿瘤的发生频率在增加。此外，NF2基因的突变和丢失 表达与散发性神经鞘瘤的发生和发展有关 脑膜瘤，提示NF2基因产物，Merlin是生长的关键 雪旺细胞和脑膜细胞的调节剂。NF2抑癌基因 与连接肌动蛋白的蛋白质4.1的序列相似 从细胞骨架到细胞表面糖蛋白。我们实验室以前的工作 已经证明，Merlin还调节细胞的运动和增殖 随着细胞的扩散。在此应用程序中，我们建议测试以下假设 Merlin集成了几个不同的细胞过程，这些过程对 细胞调节能力反映肿瘤的形成和发展 扩散(肿瘤起始)、细胞增殖(肿瘤生长)和细胞 运动性(肿瘤扩散)。本申请中提出的实验旨在 在确定Merlin肿瘤抑制因子作为负生长因子的作用时 通过定义Merlin功能结构域、关键Merlin蛋白来调节 相互作用和相关的细胞内信号通路。我们有能力 设计合理的神经鞘瘤和脑膜瘤治疗依赖于 更好地理解了Merlin表达缺失和 功能促进肿瘤的形成。