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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-连环蛋白在上皮组织中细胞-细胞粘附的形成和维持中起关键作用。它也是Wnt信号通路的重要成员，参与发育和形态发生的多个方面。Wnt信号导致β-catenin在细胞质和细胞核水平的积累，其通常通过蛋白酶体的降解过程维持在低水平。β-catenin的细胞内蓄积也见于许多人类癌症，其中已报道了β-catenin基因的各种突变。我们之前开发了一个人类疾病基因的突变数据库（Mutation View）。本研究收集了441例β-catenin基因突变病例，并将这些数据输入Mutation View。该条目清楚地表明，β-catenin基因的多种突变类型，如缺失和错义，主要发生在外显子3。特别是，错义突变影响外显子3中的丝氨酸，其通过GSK-3激酶的磷酸化参与B -连环蛋白的下调。为了理解β-连环蛋白的上调在肿瘤形成中起作用的分子机制，我们用β-连环蛋白的野生型或突变型（S33 C和S45 F）转染了四种类型的细胞系。目前，我们筛选这些野生型和突变型蛋白质含量升高的细胞系。