The transcriptional coactivator CBP interacts with beta-catenin to activate gene expression.
Beta-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 beta-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 beta-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 beta-catenin is involved in binding to CBP, whereas beta-catenin interacts directly with the CREB-binding domain of CBP. Beta-catenin synergizes with CBP to stimulate the activity of a synthetic reporter in vivo. Conversely, beta-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 beta-catenin and the transcriptional machinery, and possibly mediates the oncogenic function of beta-catenin.
Takemaru
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Howard Hughes Medical Institute, Department of Pharmacology, and Center for Developmental Biology, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Moon
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D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D050882:CREB-Binding Protein; D015820:Cadherins / Q000502:physiology; D002460:Cell Line; D003001:Cloning, Molecular; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000032:analysis; D009687:Nuclear Proteins / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology; D051176:beta Catenin
C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C093133:SIA1 protein, Xenopus; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; D051176:beta Catenin; C094620:nodal3.1 protein, Xenopus; D008156:Luciferases; D050882:CREB-Binding Protein; C494363:CREBBP protein, human