Wnt-3A/β-Catenin Signaling Induces Transcription from the LEF-1 Promoter

Abstract

Members of the Wnt family of secreted molecules have been established as key factors in determining cell fate and morphogenic signaling. It has long been recognized that Wnt induces morphogenic signaling through the Tcf/LEF-1 cascade by regulating free intracellular levels of ␤-catenin, a co-factor for Tcf/LEF-1 transcription factors. In the present study, we have demonstrated that Wnt-3A can also directly induce transcription from the LEF-1 promoter. This induction was dependent on glycogen synthase kinase 3␤ inactivation, a rise in free intracellular ␤-catenin, and a short 110-bp Wnt-responsive element (WRE) in the LEF-1 promoter. Linear and internal deletion of this WRE led to a dramatic increase in constitutive LEF-1 promoter activity and loss of Wnt-3A responsiveness. In isolation, the 110-bp WRE conferred context-independent Wnt-3A or ␤-catenin(S37A) responsiveness to a heterologous SV40 promoter. Studies expressing dominant active and negative forms of LEF-1, ␤-catenin, GSK-3␤, and ␤-catenin/ LEF-1 fusions suggest that Wnt-3A activates the LEF-1 promoter through a ␤-catenin-dependent and LEF-1-independent process. Wnt-3A expression also induced multiple changes in the binding of factors to the WRE and suggests that regulatory mechanisms may involve modulation of a multiprotein complex. In summary, these results provide evidence for transcriptional regulation of the LEF-1 promoter by Wnt and enhance the mechanistic understanding of Wnt/␤-catenin signaling in the regulation of LEF-1-dependent developmental processes.

Lymphoid Enhancer Factor-1 and ॆ-Catenin Inhibit Runx2-dependent Transcriptional Activation of the Osteocalcin Promoter

“…These data suggest that an autofeedback loop may regulate LEF1 expression in osteoblasts. Additional data in support of this autofeedback mechanism are that the canonical Wnt signaling pathway stimulates LEF1 expression (53). High levels of the Wg (Wnt) receptor Fzd2 stabilize Wg in Drosophila which, in turn decrease Fzd2 expression (54,55).…”

Upregulation of TCF4 expression as a transcriptional target of β-catenin/p300 complexes during trans-differentiation of endometrial carcinoma cells

“…For example, the b-catenin/TCF complex activates the promoter for full-length LEF1, indicating a positive feedback loop for Wnt signaling by inducing selective expression of full-length and b-catenin-sensitive forms of LEF/TCFs. 9,21 Conductin/Axin2 creates a negative loop to silence the signaling pathway following transduction of Wnt signals. 22 Moreover, deregulated b-catenin causes activation of p53, which feedbacks and downregulates b-catenin.…”

Transgenic Wnt/TCF pathway reporters: all you need is Lef?

“…For example, TGF-b pathway signaling can trigger the nuclear translocation of b-catenin in at least one cell type (Jian et al, 2006). In addition, various reports propose that b-catenin can activate Wnt target genes in a TCF-independent manner (Filali et al, 2002), that Wnts can stimulate b-catenin-independent gene activation (Ziemer et al, 2001), and that TCFs can activate transcription in the absence of Wnt signaling (Hsu et al, 1998;Labbe´et al, 2000). These types of interactions would be expected to generate either false positives or false negatives in a TCF reporter assay.…”