Brantjes H, Roose J, van De Wetering M, Clevers H
Department of Immunology, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands.
Nucleic Acids Res. 2001 Apr 1;29(7):1410-9. doi: 10.1093/nar/29.7.1410.
Tcf/Lef family transcription factors are the downstream effectors of the Wingless/Wnt signal transduction pathway. Upon Wingless/Wnt signalling, beta-catenin translocates to the nucleus, interacts with Tcf (1-3) and thus activates transcription of target genes (4,5). Tcf factors also interact with members of the Groucho (Grg/TLE) family of transcriptional co-repressors (6). We have now tested all known mammalian Groucho family members for their ability to interact specifically with individual Tcf/Lef family members. Transcriptional activation by any Tcf could be repressed by Grg-1, Grg-2/TLE-2, Grg-3 and Grg-4 in a reporter assay. Specific interactions between Tcf and Grg proteins may be achieved in vivo by tissue- or cell type-limited expression. To address this, we determined the expression of all Tcf and Grg/TLE family members in a panel of cell lines. Within any cell line, several Tcfs and TLEs are co-expressed. Thus, redundancy in Tcf/Grg interactions appears to be the rule. The 'long' Groucho family members containing five domains are repressors of Tcf-mediated transactivation, whereas Grg-5, which only contains the first two domains, acts as a de-repressor. As previously shown for Drosophila Groucho, we show that long Grg proteins interact with histone deacetylase-1. Although Grg-5 contains the GP homology domain that mediates HDAC binding in long Grg proteins, Grg-5 fails to bind this co-repressor, explaining how it can de-repress transcription.
Tcf/Lef家族转录因子是无翅型/翼状螺旋蛋白（Wingless/Wnt）信号转导通路的下游效应分子。在无翅型/翼状螺旋蛋白信号传导时，β-连环蛋白转位至细胞核，与Tcf（1 - 3）相互作用，从而激活靶基因的转录（4,5）。Tcf因子还与转录共抑制因子Groucho（Grg/TLE）家族的成员相互作用（6）。我们现已检测了所有已知的哺乳动物Groucho家族成员与各个Tcf/Lef家族成员特异性相互作用的能力。在报告基因检测中，Grg - 1、Grg - 2/TLE - 2、Grg - 3和Grg - 4可抑制任何Tcf介导的转录激活。Tcf与Grg蛋白之间的特异性相互作用可能通过组织或细胞类型限制表达在体内实现。为解决这一问题，我们测定了一组细胞系中所有Tcf和Grg/TLE家族成员的表达情况。在任何一个细胞系中，几种Tcf和TLE是共表达的。因此，Tcf/Grg相互作用中的冗余似乎是常态。含有五个结构域的“长”Groucho家族成员是Tcf介导的反式激活的抑制因子，而仅含有前两个结构域的Grg - 5则作为去抑制因子发挥作用。正如先前对果蝇Groucho所显示的那样，我们发现长Grg蛋白与组蛋白去乙酰化酶 - 1相互作用。尽管Grg - 5含有在长Grg蛋白中介导HDAC结合的GP同源结构域，但Grg - 5未能结合这种共抑制因子，这就解释了它如何能够去抑制转录。
