Brantjes Helen, Barker Nick, van Es Johan, Clevers Hans
Department of Immunology, University Hospital Utrecht, The Netherlands.
Biol Chem. 2002 Feb;383(2):255-61. doi: 10.1515/BC.2002.027.
The Wnt signalling cascade plays an important role during embryonic patterning and cell fate determination and is highly conserved throughout evolution. Factors of the TCF/LEF HMG domain family (Tcfs) are the downstream effectors of this signal transduction pathway. Upon Wnt signalling, a cascade is initiated that results in the translocation of beta-catenin to the nucleus, where it interacts with Tcf to generate a transcriptionally active complex. This bipartite transcription factor is targeted to the upstream regulatory regions of Tcf target genes. In the absence of Wnt signals, beta-catenin is degraded in the cytoplasm via the ubiquitin-proteasome pathway. Several proteins are instrumental in achieving this tight regulation of beta-catenin levels in the cell, including adenomatous polyposis coli (APC), GSK3 beta, and Axin/Conductin. Deregulation of the Wnt signalling pathway is implicated in several forms of cancer, such as colon carcinoma and melanoma. This deregulation is achieved via mutation of APC, beta-catenin or Axin, resulting in elevated beta-catenin levels and the presence of constitutively active Tcf-beta-catenin complexes in the nucleus. The accompanying inappropriate activation of target genes is considered to be a critical, early event in this carcinogenesis. In addition to regulating beta-catenin levels, normal healthy cells have evolved a second level of regulation, by manipulating the activity of the Tcf proteins themselves. In the absence of Wnt signalling, Tcf complexes with several transcriptional repressor proteins ensuring active repression of Tcf target genes. In this review the dual role of Tcf proteins in the Wnt signalling cascade will be discussed.
Wnt信号级联反应在胚胎模式形成和细胞命运决定过程中发挥着重要作用，并且在整个进化过程中高度保守。TCF/LEF HMG结构域家族（Tcfs）的因子是该信号转导途径的下游效应器。在Wnt信号作用下，会启动一个级联反应，导致β-连环蛋白转运至细胞核，在细胞核中它与Tcf相互作用形成转录活性复合物。这种二元转录因子靶向于Tcf靶基因的上游调控区域。在没有Wnt信号时，β-连环蛋白通过泛素-蛋白酶体途径在细胞质中降解。几种蛋白质有助于实现对细胞中β-连环蛋白水平的严格调控，包括腺瘤性息肉病大肠杆菌（APC）、糖原合成酶激酶3β（GSK3β）和轴蛋白/传导素（Axin/Conductin）。Wnt信号通路的失调与多种癌症形式有关，如结肠癌和黑色素瘤。这种失调是通过APC、β-连环蛋白或Axin的突变实现的，导致β-连环蛋白水平升高以及细胞核中持续存在有活性的Tcf-β-连环蛋白复合物。伴随的靶基因不适当激活被认为是这种致癌过程中的一个关键早期事件。除了调节β-连环蛋白水平外,正常健康细胞还通过操纵Tcf蛋白自身的活性进化出了第二种调节水平。在没有Wnt信号时，Tcf与几种转录抑制蛋白形成复合物，确保对Tcf靶基因的有效抑制。在这篇综述中，将讨论Tcf蛋白在Wnt信号级联反应中的双重作用。
