1. ¹Inserm, U762, Paris, F-75010, France
2. ²Univ Paris 6, Paris, F-75005, France
3. ³Imagerie Cellulaire Et Microscopie Confocale, IFR 65, Hôpital Tenon, Paris, France

Correspondence: Dr A Duval, INSERM U762, 27 rue Juliette Dodu, 75010 Paris, France. E-mail: alex.duval@cephb.fr

⁴These authors contributed equally to this work.

Received 7 September 2005; Revised 14 December 2005; Accepted 24 January 2006; Published online 20 March 2006.

Abstract

TCF-4 is the main effector of the Wnt/Wingless signalling pathway. As with other TCF/LEF factors, numerous alternative splicings at its 3' end affect its expression. Such a mechanism leads to the synthesis of numerous TCF-4 isoforms among which some contain binding domains for CtBP, an ubiquitous transcriptional corepressor. Of interest, we described a frequent TCF-4 frameshift mutation in mismatch-repair deficient colorectal cancers (MSI-H cancers) that leads to the selective loss of TCF-4 isoforms with CtBP binding abilities. We provide here data that argue for a partial colocalization of CtBP with TCF-4 isoforms containing CtBP binding domains in cellulo, and for a functional role of CtBP in repressing TCF-4 mediated transcription. We also demonstrate that such a colocalization is not observed in MSI-H colorectal cancer cells that harbour the TCF-4 frameshift mutation, and that CtBP is not able to repress TCF-4-mediated transcription in this context. Taken together, our results strongly suggest that CtBP would play a role in regulating TCF-4 mediated transcription upon its binding with some TCF-4 isoforms encoded by alternatively spliced mRNA. They also suggest a role for TCF-4 frameshift mutation during MSI-H colorectal tumour progression, by regulating the relative proportion of the different TCF-4 isoforms.