FUNCTIONAL EVALUATION OF 0 -CATENIN GENE MUTATIONS IN TUMOR DEVELOPMENT : EFFECTS OF β-CATENIN MUTANTS ON CELL MOTILITY AND GENE EXPRESSION

0-连环蛋白基因突变在肿瘤发展中的功能评估：β-连环蛋白突变体对细胞运动和基因表达的影响

基本信息

批准号：
11672200
负责人：
TAKEUCHI Kenji
金额：
$ 2.3万
依托单位：
SETSUNAN UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672200/
关键词：
β-catenin Wnt Tumor Gene mutation Mutation database バルプロ酸 Axin がん GSK-3 カドヘリンガン細胞接着遺伝子発現

项目摘要

β-catenin plays a crucial role in the formation and maintenance of cell-cell adhesions in epithelial tissues. It is also an important member of Wnt signaling pathway that is involved in several aspects of development and morphogenesis. Wnt signal results in the accumulation of cytosolic and nuclear levels of β-catenin, which is normally maitained at a low level through the degradation process via proteasome. Intracellualr accumulation of β-catenin is also found in a number of human cancers where a variety of mutations in β-catenin gene have been reported. We previously developed a mutation database (Mutation View) for human disease genes. In this study, we have collected 441 cases for the mutation of β-catenin gene and entered these data into Mutation View. This entry clearly shows us that a variety of mutation types such as deletion and missense occur maily in exon 3 of β-catenin gene. Especially, the missense mutations affect serines in exon 3 that have been implicated in the down-regulation of B -catenin through phosphorylation by the GSK-3 kinase. To understand the molecular mechanism by which up-regulation of β-catenin plays a role in tumor formation, we transfected four types of cell lines with wild type or mutant types (S33C and S45F) of β-catenin. At present, we screen cell lines with elevated amounts of these wild and mutant proteins.

β-catenin在上皮组织的细胞细胞粘附形成和维持中起着至关重要的作用。它也是Wnt信号通路的重要成员，它参与了发育和形态发生的几个方面。 Wnt信号会导致β-catenin的胞质和核水平的积累，通常通过蛋白酶体在降解过程中以低水平培养。在许多人类癌症中还发现了β-catenin的细胞内积累，其中已经报道了β-catenin基因中的各种突变。我们以前开发了针对人类疾病基因的突变数据库（突变视图）。在这项研究中，我们收集了441例β-catenin基因突变的病例，并将这些数据输入突变视图。该条目清楚地表明，在β-catenin基因的外显子3中，多种突变类型，例如缺失和错义邮件。尤其是，错义突变会影响外显子3中的丝氨酸，这些丝氨酸通过GSK-3激酶通过磷酸化在B-蛋白质下降中实施。为了了解β-catenin在肿瘤形成中起作用的分子机制，我们转染了β-蛋白的四种类型的野生型或突变类型或突变类型（S33C和S45F）的细胞系。目前，我们筛选了这些野生和突变蛋白量升高的细胞系。