C-terminal-binding protein directly activates and represses Wnt transcriptional targets in Drosophila

Abstract

Regulation of Wnt transcriptional targets is thought to occur by a transcriptional switch. In the absence of Wnt signaling, sequence‐specific DNA‐binding proteins of the TCF family repress Wnt target genes. Upon Wnt stimulation, stabilized β‐catenin binds to TCFs, converting them into transcriptional activators. C‐terminal‐binding protein (CtBP) is a transcriptional corepressor that has been reported to inhibit Wnt signaling by binding to TCFs or by preventing β‐catenin from binding to TCF. Here, we show that CtBP is also required for the activation of some Wnt targets in Drosophila. CtBP is recruited to Wnt‐regulated enhancers in a Wnt‐dependent manner, where it augments Armadillo (the fly β‐catenin) transcriptional activation. We also found that CtBP is required for repression of a subset of Wnt targets in the absence of Wnt stimulation, but in a manner distinct from previously reported mechanisms. CtBP binds to Wnt‐regulated enhancers in a TCF‐independent manner and represses target genes in parallel with TCF. Our data indicate dual roles for CtBP as a gene‐specific activator and repressor of Wnt target gene transcription.

Involvement of CtBP1 in the transcriptional activation of the MDR1 gene in human multidrug resistant cancer cells

“…Furthermore, recent study shows that CtBP can not only repress, but also activate gene transcription. It has been shown that in addition to repressing a subset of Wnt target genes in the absence of Wnt stimulation, CtBP also causes transcriptional activation of several genes upon Wnt stimulation (20). We report here that CtBP1 participates in transcriptional activation of the MDR1 gene through direct interaction with the MDR1 promoter, and inhibition of CtBP1 expression can enhance sensitivity of MDR cancer cells to certain chemotherapeutic drugs.…”

“…Recently, the function of CtBP as a transcriptional activator has also been reported for Wnt target genes. It was demonstrated that CtBP direct activates Wnt transcriptional targets through its interaction with the Wnt-regulated enhancer of the genes (20). Therefore, it appears that CtBP1 is a "dual" regulator, i.e., activator and repressor of transcription, and inhibiting or activating gene transcription by CtBP appears to be context-dependent.…”

Role of Pinin in neural crest, dorsal dermis, and axial skeleton development and its involvement in the regulation of Tcf/Lef activity in mice

“…Additionally, CtBPs can also interact with APC tumor suppressor protein to divert active nuclear ␤-catenin away from TCFs (Hamada and Bienz, 2004;Sierra et al, 2006). Furthermore, CtBP has been recently shown to directly activate or repress Wnt target genes in a TCF-independent manner in Drosophila, increasing the complexity of the Wnt signaling mechanism (Fang et al, 2006). Thus, the interaction between PNN and CtBP may provide a focal point for investigating PNN's role in the regulation of Wnt/␤-catenin signaling.…”

The microRNA miR-8 is a conserved negative regulator of Wnt signaling

“…2A) and activates target genes such as Distal-less (Dll, Fig. 2B) (10,13). Expression of miR-8 along the anterior-posterior boundary of the wing pouch using decapentaplegic (dpp)-Gal4 dramatically reduced Dll expression, as visualized by a loss of Dll-lacZ reporter expression in this domain (Fig.…”

“…1B). To identify regulators of the Wg pathway, we performed a genetic screen to identify genes that, when misexpressed, suppress this small-eye phenotype (10,11). Wg was coexpressed with random genes that were placed under the control of bidirectional Gal4-dependent (UAS) promoters by GSV transposable element insertions (12).…”