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

β-连环蛋白在上皮组织细胞间黏附的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，参与发育和形态发生的多个方面。WNT信号导致胞浆和胞核中β-连环蛋白的积累，通常通过蛋白酶体的降解过程将其维持在较低的水平。β-连环蛋白在细胞内的积聚也在一些人类癌症中被发现，其中β-连环蛋白基因的各种突变已被报道。我们之前开发了一个人类疾病基因的突变数据库(突变视图)。在本研究中，我们收集了441例β-连环蛋白基因突变的病例，并将这些数据输入到突变视图中。这个条目清楚地告诉我们，β-catenin基因外显子3主要发生缺失和错义等多种突变类型。特别是，错义突变影响外显子3的丝氨酸，该外显子通过GSK-3激酶的磷酸化而下调B-连环蛋白的表达。为了了解β-连环蛋白上调在肿瘤形成中的分子机制，我们用野生型和突变型β-连环蛋白(S33C和S45F)分别转染了四种类型的细胞系。目前，我们筛选出这些野生型和突变型蛋白含量升高的细胞系。

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.