FUNCTIONAL ANALYSIS OF NF2 GENE MUTATIONS

NF2基因突变的功能分析

• 批准号: 6613409
• 负责人: David H Gutmann
• 金额: $ 30.8万
• 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 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613409
• 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（来自申请人的摘要）：关于 神经系统肿瘤如脑膜瘤和 神经鞘瘤患有神经纤维瘤病2（NF2）的人会出现这些症状。 肿瘤的发生频率越来越高。此外，NF2基因的突变和缺失 表达与散发性神经鞘瘤的发生有关， 脑膜瘤，表明NF2基因产物，梅林是一个关键的增长 雪旺细胞和脑膜细胞的调节剂。NF2肿瘤抑制基因 与连接肌动蛋白的蛋白质4.1具有序列相似性， 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也调节细胞运动和增殖 as cell细胞spreading传播.在本申请中，我们提出测试以下假设： merlin整合了几种不同的细胞过程， 肿瘤的形成和发展通过其调节细胞的能力来反映， 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 在确定梅林肿瘤抑制因子如何作为负生长 通过定义merlin功能结构域，关键merlin蛋白 相互作用和相关的细胞内信号通路。的能力 设计神经鞘瘤和脑膜瘤的合理治疗方法取决于 提高了对merlin表达缺失的机制的理解， 功能促进肿瘤形成。

项目成果

Characterization of chicken Nf2/merlin indicates regulatory roles in cell proliferation and migration.

鸡 Nf2/merlin 的表征表明其在细胞增殖和迁移中的调节作用。

• DOI: 10.1002/dvdy.20002
• 发表时间: 2004
• 期刊: Developmental dynamics : an official publication of the American Association of Anatomists.
• 作者: Chen,Y;Gutmann,DH;Haipek,CA;Martinsen,BJ;Bronner-Fraser,M;Krull,CE
• 通讯作者: Krull,CE

Merlin: hanging tumor suppression on the Rac.

Merlin：在Rac上挂肿瘤抑制。

• DOI: 10.1016/s0962-8924(01)02128-6
• 发表时间: 2001
• 期刊: Trends in cell biology
• 影响因子: 19
• 作者: Sherman,LS;Gutmann,DH
• 通讯作者: Gutmann,DH

Functional analysis of the relationship between the neurofibromatosis 2 tumor suppressor and its binding partner, hepatocyte growth factor-regulated tyrosine kinase substrate.

神经纤维瘤病 2 肿瘤抑制因子与其结合伴侣、肝细胞生长因子调节的酪氨酸激酶底物之间关系的功能分析。

• DOI: 10.1093/hmg/11.25.3167
• 发表时间: 2002
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Sun,Chun-Xiao;Haipek,Carrie;Scoles,DanielR;Pulst,StefanM;Giovannini,Marco;Komada,Masayuki;Gutmann,DavidH
• 通讯作者: Gutmann,DavidH

Neurofibromatosis 2 tumor suppressor protein, merlin, forms two functionally important intramolecular associations

• DOI: 10.1002/(sici)1097-4547(19991201)58:5<706::aid-jnr12>3.0.co;2-z
• 发表时间: 1999-12-01
• 期刊: JOURNAL OF NEUROSCIENCE RESEARCH
• 影响因子: 4.2
• 作者: Gutmann, DH;Haipek, CA;Lu, KH
• 通讯作者: Lu, KH