The NF2 gene: elucidation of tumor suppressor function

NF2基因：阐明肿瘤抑制功能

• 批准号: 6648978
• 负责人: JOSEPH KISSIL
• 金额: $ 4.81万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6648978
• 关键词: biological signal transduction; cell proliferation; genetic models; laboratory mouse; neoplasm /cancer genetics; nerve /myelin protein; neurofibromatosis; phosphorylation; postdoctoral investigator; protein isoforms; protein protein interaction; protein structure function; serine threonine protein kinase; tumor suppressor proteins

DESCRIPTION (provided by applicant): Neurofibromatosis type 2 (NF2) is an inherited disorder characterized by development of Schwann cell tumors of the eighth cranial nerve. The NF2 gene codes for a protein highly related to the ERM proteins moesin, ezrin and radixin and was thus termed merlin. The ERM proteins are thought to function as cell membrane-cytoskeleton linkers. Merlin is regulated, at least in part, by Rac/cdc42-dependent phosphorylation. Recent data implicates merlin as a possible negative regulator of the Rac/cdc42 signaling pathway. The proposed project focuses on the study of the tumor suppressive properties of merlin and the signaling pathways connecting extracellular signals to cytoskeletal organization and/or the proliferative state of the cell, via merlin. The work involves two combined approaches: 1) Understanding how merlin might interact with and regulate, the Rac/cdc42 signaling pathway. 2) Structure/function studies of merlin involving introduction of isoforms and mutated forms of the protein into Nf2-deficient cells. Specifically, mutations effecting merlin phosphorylation will be examined. The proposed project should shed light on the growth suppressive effects of merlin and possible cross-talk with the Rac/cdc42 pathway. This should lead to a better understanding of merlin function in normal cells and the consequences of its loss in tumor development. Such information will directly assist in the search for effective therapies.

描述(申请人提供)：神经纤维瘤病2型(NF2)是一种遗传性疾病，其特征是发展为第八脑神经的雪旺细胞瘤。NF2基因编码一种与ERM蛋白moesin、ezrin和Radixin高度相关的蛋白质，因此被称为Merlin。ERM蛋白被认为是细胞膜-细胞骨架连接物。Merlin至少部分受RAC/Cdc42依赖的磷酸化调控。最近的数据表明，Merlin可能是RAC/CDC42信号通路的负调控因子。该项目的重点是研究Merlin的肿瘤抑制特性，以及通过Merlin将细胞外信号与细胞骨架组织和/或细胞增殖状态联系起来的信号通路。这项工作涉及两个结合的方法：1)了解Merlin可能如何与RAC/CDC42信号通路相互作用和调节。2)Merlin的结构/功能研究，包括将该蛋白的异构体和突变形式导入NF2缺陷细胞。具体地说，将检测影响Merlin磷酸化的突变。拟议的项目应该有助于阐明Merlin对生长的抑制作用，以及可能与RAC/CDC42途径的相互作用。这应该有助于更好地理解Merlin在正常细胞中的功能以及它在肿瘤发展过程中丢失的后果。这些信息将直接帮助寻找有效的治疗方法。