Molecular Function of the Nf2 Tumor Suppressor, Merlin

Nf2 肿瘤抑制因子 Merlin 的分子功能

基本信息

批准号：
7254767
负责人：
ANDREA I MCCLATCHEY
金额：
$ 22.63万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7254767
关键词：
Actins Adherens Junction Adhesions Affect Animal Model Appendix Benign Cadherins Cell Communication Cell Density Cell Proliferation Cells Central Nervous System Neoplasms Class Clinical Treatment Clinical Trials Communication Complex Cytoskeleton Development Disseminated Malignant Neoplasm Embryo Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Family member Foundations Goals Growth Hereditary Malignant Neoplasm Human In Vitro Link Localized Malignant Neoplasms Measures Mediating Membrane Molecular Monitor Mus Mutant Strains Mice Mutation Neoplasm Metastasis Neurofibromatosis 2 Neurofibromin 2 Numbers Patients Play Post-Translational Protein Processing Process Proteins Receptor Protein-Tyrosine Kinases Receptor Signaling Recruitment Activity Role Signal Transduction Source Staging Structure Syndrome Testing Therapeutic Intervention Thinking Tumor Suppressor Genes Tumor Suppressor Proteins cell type ezrin in vivo insight interest membrane assembly moesin mouse model mutant neoplastic cell novel radixin protein receptor downregulation receptor internalization tool tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Mutations in the NF2 tumor suppressor gene underlie Neurofibromatosis type 2 (NF2), a familial cancer syndrome featuring the development of central nervous system tumors. The NF2-encoded protein, Merlin, is closely related to the ERM (Ezrin, Radixin and Moesin) proteins, which are thought to facilitate the assembly of membrane:actin cytoskeleton complexes. However, the mechanism whereby Merlin controls cell proliferation is not known. To create an animal model for Nf2-associated tumorigenesis and develop tools for defining the molecular function of Merlin, we generated an Nf2-mutant strain of mice and found that Nf2 mutation predisposes mice to a variety of highly metastatic cancers. This is surprising given the limited spectrum of benign tumors in human NF2 patients and suggests that Nf2 inactivation may play an unrecognized role in cancer development and progression. Our broad objective is to use Nf2-mutant mice and cells to delineate the function of Merlin and its family members in cancer development and progression. We have recently found that a signature of Nf2-deficiency across several types of primary cells is loss of contact-dependent inhibition of proliferation and lack of normal cadherin-mediated cell:cell communication. We discovered that Merlin localizes to cadherin-containing adherens junctions (AJs) in wild-type cells and is required for the establishment of the final actin cytoskeleton associated AJ structure. We also found that silencing of the epidermal growth factor receptor (EGFR) at high cell density, which is known to be mediated by AJ establishment, is defective in the absence of Merlin. The goals of this proposal are to determine whether control of AJ establishment and EGFR silencing is the cellular mechanism whereby Merlin acts as a tumor and metastasis suppressor and to delineate the mechanism of Merlin function in AJ establishment. The results of this study will yield important insight into the mechanism of Merlin function as a tumor suppressor and identify novel targets for therapeutic intervention of NF2.

描述（由申请人提供）：NF2肿瘤抑制基因突变是2型神经纤维瘤病（NF2）的基础，这是一种以中枢神经系统肿瘤发展为特征的家族性癌症综合征。 NF2 编码蛋白 Merlin 与 ERM（Ezrin、Radixin 和 Moesin）蛋白密切相关，这些蛋白被认为有助于膜：肌动蛋白细胞骨架复合物的组装。然而，Merlin 控制细胞增殖的机制尚不清楚。为了创建 Nf2 相关肿瘤发生的动物模型并开发定义 Merlin 分子功能的工具，我们培育了 Nf2 突变小鼠品系，发现 Nf2 突变使小鼠易患多种高度转移性癌症。鉴于人类 NF2 患者良性肿瘤的范围有限，这一结果令人惊讶，并表明 Nf2 失活可能在癌症发生和进展中发挥着未被认识到的作用。我们的总体目标是使用 Nf2 突变小鼠和细胞来描述 Merlin 及其家族成员在癌症发生和进展中的功能。我们最近发现，几种类型的原代细胞缺乏 Nf2 的特征是接触依赖性增殖抑制的丧失以及正常钙粘蛋白介导的细胞间通讯的缺乏。我们发现 Merlin 定位于野生型细胞中含有钙粘蛋白的粘附连接 (AJ)，并且是建立最终肌动蛋白细胞骨架相关 AJ 结构所必需的。我们还发现，高细胞密度下表皮生长因子受体（EGFR）的沉默（已知是由 AJ 建立介导的）在缺乏 Merlin 的情况下是有缺陷的。该提案的目标是确定 AJ 建立和 EGFR 沉默的控制是否是 Merlin 作为肿瘤和转移抑制剂发挥作用的细胞机制，并描述 Merlin 在 AJ 建立中的功能机制。这项研究的结果将有助于深入了解 Merlin 作为肿瘤抑制因子的作用机制，并确定 NF2 治疗干预的新靶点。