Discussion

We show that Edar inhibit Wnt/(-catenin signalling. We confirm the results previously reported by Chaudarry et al., 2004. Wnt/(-catenin is involved in both cell adhesion and cellular signalling as a mediator of Wingless/Wnt-dependent signal transduction (ref). Axin/Conductin, in cooperation with the tumor suppressor gene product APC ( ) promote (-catenin degradation, which involves serine-threonine phosphorylation on the N-terminus of (-catenin by GSK3( and subsequent ubiquitination and degradation. (-catenin/Lef-TCF signalling is initiated by binding of extracellular Wnt ligands to their respective receptors of the Frizzled (Fz) family, using LRP membrane-bound co-receptors, members of the low density lipoprotein receptor-related protein family. This binding prevent (-catenin degradation which accumulates and translocate into nucleus where it interact with transcription factor of the T cell factor/Lymphoid enhancer factor family (TCF/Lef) to activate the target Wnt-responsive genes (Gordon and Nusse, 2006). In our experiments, we used a (-catenin form (S45Y) which is mutated in serine 45, the phosphorylation target site. This (-catenin form in not phosphorylated, escape degradation, is present continuously into the nucleus and is constitutively active. The transfection of this mutated form together with Edar or its adapter EDARADD inhibit severely its transcriptional activity. We further confirmed the inhibition of Wnt/(-catenin signalling by Edar in two cancerous cell lines where the endogenous (-catenin is constitutively active. HepG2 are human hepatic carcinoma-derived cells which carry a deletion in (-catenin gene which removes the NH-2 terminal region (amino acids 25-140) containing the GSK-3( phosphorylation site (De La Coste A et al., 1998). SW480 are human colorectal tumor-derived cells which carry a mutation in the APC gene. In both cell lines, the transfection of Edar, Edaradd or both is able to significantly inhibit the transcriptional