Department of Medicine, Division of Hematology Oncology, University of California Irvine Medical Center, Orange, CA, USA.
Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, CA, USA.
Br J Pharmacol. 2017 Dec;174(24):4589-4599. doi: 10.1111/bph.13963. Epub 2017 Aug 24.
The highly conserved Wnt signalling pathway plays an important role in embryonic development and disease pathogenesis, most notably cancer. The 'canonical' or β-catenin-dependent Wnt signal initiates at the cell plasma membrane with the binding of Wnt proteins to Frizzled:LRP5/LRP6 receptor complexes and is mediated by the translocation of the transcription co-activator protein, β-catenin, into the nucleus. β-Catenin then forms a complex with T-cell factor (TCF)/lymphoid enhancer binding factor (LEF) transcription factors to regulate multiple gene programmes. These programmes play roles in cell proliferation, migration, vasculogenesis, survival and metabolism. Mutations in Wnt signalling pathway components lead to constitutively active Wnt signalling that drives aberrant expression of these programmes and development of cancer. It has been a longstanding and challenging goal to develop therapies that can interfere with the TCF/LEF-β-catenin transcriptional complex. This review will focus on the (i) structural considerations for targeting the TCF/LEF-β-catenin and co-regulatory complexes in the nucleus, (ii) current molecules that directly target TCF/LEF-β-catenin activity and (iii) ideas for targeting newly discovered components of the TCF/LEF-β-catenin complex and/or downstream gene programmes regulated by these complexes.
This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.
高度保守的 Wnt 信号通路在胚胎发育和疾病发病机制中发挥着重要作用，尤其是在癌症中。“经典”或β-连环蛋白依赖性 Wnt 信号起始于细胞膜，Wnt 蛋白与 Frizzled：LRP5/LRP6 受体复合物结合，并通过转录共激活蛋白β-连环蛋白转位到细胞核内而介导。β-连环蛋白随后与 T 细胞因子（TCF）/淋巴增强结合因子（LEF）转录因子形成复合物，以调节多个基因程序。这些程序在细胞增殖、迁移、血管生成、存活和代谢中发挥作用。Wnt 信号通路成分的突变导致组成性激活的 Wnt 信号，驱动这些程序的异常表达和癌症的发展。长期以来，开发能够干扰 TCF/LEF-β-连环蛋白转录复合物的治疗方法一直是一个具有挑战性的目标。这篇综述将重点介绍（i）靶向细胞核中 TCF/LEF-β-连环蛋白和共调节复合物的结构考虑因素，（ii）直接靶向 TCF/LEF-β-连环蛋白活性的现有分子，以及（iii）靶向 TCF/LEF-β-连环蛋白复合物新发现成分和/或受这些复合物调节的下游基因程序的想法。
本文是 WNT 信号：机制和治疗机会专题的一部分。要查看该部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.
