The NF2 gene: elucidation of tumor suppressor function

NF2基因：阐明肿瘤抑制功能

• 批准号: 6747904
• 负责人: JOSEPH KISSIL
• 金额: $ 2.29万
• 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 2004-10-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6747904
• 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（由申请人提供）：2型神经纤维瘤病（NF 2）是一种遗传性疾病，其特征为第八脑神经的许旺细胞瘤的发展。NF 2基因编码与ERM蛋白膜突蛋白、埃兹蛋白和根蛋白高度相关的蛋白质，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/cdc 42依赖性磷酸化的调节。最近的数据暗示梅林作为一个可能的负调节Rac/cdc 42信号通路。该项目的重点是研究梅林的肿瘤抑制特性，以及通过梅林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。这项工作涉及两种结合的方法：1）了解梅林如何与Rac/cdc 42信号通路相互作用和调节。2)merlin的结构/功能研究涉及将该蛋白的亚型和突变形式引入Nf 2缺陷细胞中。具体而言，将检查影响merlin磷酸化的突变。拟议的项目应阐明梅林的生长抑制作用和可能的串扰与Rac/cdc 42途径。这将使我们更好地理解正常细胞中merlin的功能，以及它在肿瘤发展中丧失的后果。这些信息将直接有助于寻找有效的治疗方法。