The Transcriptional Coactivator Cbp Interacts with β-Catenin to Activate Gene Expression

Abstract

β-Catenin plays a pivotal role in the transcriptional activation of Wnt-responsive genes by binding to TCF/LEF transcription factors. Although it has been suggested that the COOH-terminal region of β-catenin functions as an activation domain, the mechanisms of activation remain unclear. To screen for potential transcriptional coactivators that bind to the COOH-terminal region of β-catenin, we used a novel yeast two-hybrid system, the Ras recruitment system (RRS) that detects protein–protein interactions at the inner surface of the plasma membrane. Using this system, we isolated the CREB-binding protein (CBP). Armadillo (Arm) repeat 10 to the COOH terminus of β-catenin is involved in binding to CBP, whereas β-catenin interacts directly with the CREB-binding domain of CBP. β-Catenin synergizes with CBP to stimulate the activity of a synthetic reporter in vivo. Conversely, β-catenin–dependent transcriptional activation is repressed by E1A, an antagonist of CBP function, but not by an E1A mutant that does not bind to CBP. The activation of Wnt target genes such as siamois and Xnr3 in Xenopus embryos is also sensitive to E1A. These findings suggest that CBP provides a link between β-catenin and the transcriptional machinery, and possibly mediates the oncogenic function of β-catenin.

Physical and functional cooperation between AP-1 and β-catenin for the regulation of TCF-dependent genes

“…The physical interaction between b-catenin and both c-Jun and c-Fos was demonstrated by co-immunoprecipitations in vivo and by glutathione S-transferase (GST) pull-down assays in vitro. The co-immunoprecipitation experiments do not directly prove that the b-catenin interaction with AP-1 proteins was direct, because b-catenin has been reported previously to bind other proteins that are also potential partners of c-Jun and c-Fos, such as CBP/p300 (Miyagishi et al, 2000;Takemaru and Moon, 2000;Harris and Peifer, 2005) or the LIM-only protein (Morlon and Sassone-Corsi, 2003). However, our in vitro pull-down assays clearly demonstrate a direct association between the armadillo repeats of b-catenin and the DNA-binding domain of c-Jun and the C-terminal domain of b-catenin with the N-terminal region of c-Fos.…”

“…Binding of b-catenin to LEF/TCF causes displacement of core-repressor complexes containing histone deacetylases (Billin et al, 2000), and heterodimerization that allows interaction with the C-terminal transactivation domain of b-catenin leading ultimately to the activation of transcription of Wntresponsive genes Moon et al, 2002). The coactivator function of b-catenin is induced by recruitment of the basal transcription machinery (Hecht et al, 1999) and is enhanced by synergistic cooperation with a number of other proteins such as coactivators, (Zhurinsky et al, 2000;Martin et al, 2002;Grueneberg et al, 2003;Wei et al, 2003) or proteins involved in chromatin remodeling and histone modification (Hecht et al, 2000;Miyagishi et al, 2000;Sun et al, 2000;Takemaru and Moon, 2000;Barker et al, 2001). Not surprisingly, mounting evidence indicate that b-catenin is able to cross-talk with a variety of signalling cascades, such as those involving Rac GTPase, forkhead box O transcription factors or transforming growth factor (TGF)b (Eger et al, 2004;Esufali and Bapat, 2004;Chakladar et al, 2005;Essers et al, 2005).…”

Cell type‐ and promoter‐dependent modulation of the Wnt signaling pathway by sodium butyrate

“…59 Further study is necessary to delineate the role, if any, of TLE factors in the de-repression of Wnt activity in butyrate-treated HCT-116 cells. In addition, we determined that overexpression of CBP, implicated in the control of Wnt activity, 50,53 does not influence butyrate modulation of the Wnt signaling pathway in HCT-116 cells (data not shown). In summary, the mechanisms by which Tcf cofactors may influence Wnt activity in butyrate-treated HCT-116 cells are as yet undetermined.…”

Wnt signaling in disease and in development

“…This may occur through displacement of Groucho from TCF/LEF and recruitment of the histone acetylase CBP/p300. CBP may bind to the β-catenin-TCF complex as a co-activator [26,27], a hypothesis that remains to be tested directly. Another activator, Brg-1, is a component of the SWI/SNF chromatin remodeling complex which, with CBP, may induce chromatin remodeling that favors target gene transcription [28].…”