beta-Catenin plays a dual role as a regulatory component of adherens junctions and as a transcriptional cofactor. The nuclear activity of this protein is controlled by adenomatous polyposis coli (APC) protein. We have analyzed the effect on beta-catenin-de- pendent transcription of a beta-catenin binding domain present in APC, consisting in three 15-amino acid repeats (APC 3 x 15). Association of this fragment prevents the interaction of beta-catenin with E-cadherin but not with TCF-4. Transfection of this fragment to several cell lines increases the transcriptional activity of the beta-catenin-TCF-4 complex and promotes the translocation of beta-catenin to the nucleus. Moreover, previous binding of APC 3 x 15 facilitates the association of beta-catenin to the TATA box-associated protein. Therefore, APC 3 x 15 domain plays a positive role in the control of transcriptional activity of beta-catenin-TCF-4 and can contribute to explain the role of the truncated forms of APC in colon tumorigenesis. (C) 2003 Elsevier Inc. All rights reserved.