Clevers H, van de Wetering M
Department of Immunology, University Hospital Utrecht, The Netherlands.
Trends Genet. 1997 Dec;13(12):485-9. doi: 10.1016/s0168-9525(97)01305-x.
Factors of the TCF/LEF HMG domain family (TCFs) exist in vertebrates, Drosophila melanogaster and Caenorhabditis elegans. It has very recently become evident that TCFs interact with the vertebrate WNT effector beta-catenin to mediate axis formation in Xenopus. Likewise, Armadillo (the Drosophila ortholog of beta-catenin) is genetically upstream of a Drosophila TCF in the Wingless pathway. Upon Wingless/Wnt signaling, Armadillo/beta-catenin associate with nuclear TCFs and contribute a trans-activation domain to the resulting bipartite transcription factor. The cytoplasmic tumor-suppressor protein APC binds to beta-catenin causing its destruction. In APC-deficient colon carcinoma cells, beta-catenin accumulates and is constitutively complexed with TCF factors. In APC-positive colon carcinomas and melanomas, dominant mutations in beta-catenin render it indestructable, providing an alternative mechanism to activate transcription of TCF target genes inappropriately. So, transcriptional activation of TCF target genes by beta-catenin appears to be a central event in development and cellular transformation.
TCF/LEF HMG结构域家族（TCFs）的因子存在于脊椎动物、黑腹果蝇和秀丽隐杆线虫中。最近很明显的是，TCFs与脊椎动物WNT效应因子β-连环蛋白相互作用，以介导非洲爪蟾的轴形成。同样，犰狳（β-连环蛋白的果蝇直系同源物）在无翅通路中位于果蝇TCF的遗传上游。在无翅/Wnt信号传导时，犰狳/β-连环蛋白与核TCFs结合，并为产生的二分体转录因子贡献一个反式激活结构域。细胞质肿瘤抑制蛋白APC与β-连环蛋白结合导致其降解。在APC缺陷的结肠癌细胞中，β-连环蛋白积累并与TCF因子持续形成复合物。在APC阳性的结肠癌和黑色素瘤中，β-连环蛋白的显性突变使其无法降解，提供了一种不适当激活TCF靶基因转录的替代机制。因此，β-连环蛋白对TCF靶基因的转录激活似乎是发育和细胞转化中的一个核心事件。
