Abstract

beta-Catenin is a cytoplasmic protein that participates in the assembly of cell-cell adherens junctions by binding cadherins to the actin cytoskeleton. In addition, it is a key component of the Wnt signaling pathway. Activation of this pathway triggers the accumulation of beta-catenin in the nucleus, where it activates the transcription of target genes. Abnormal accumulation of beta-catenin is characteristic of various types of cancer and is caused by mutations either in the adenomatous polyposis coli protein, which regulates beta-catenin degradation, or in the beta-catenin molecule itself. Aberrant accumulation of beta-catenin in tumors is often associated with mutational inactivation of the p53 tumor suppressor. Here we show that overexpression of wild-type p53, by either transfection or DNA damage, down-regulates beta-catenin in human and mouse cells. This effect was not obtained with transcriptionally inactive p53, including a common tumor-associated p53 mutant. The reduction in beta-catenin level was accompanied by inhibition of its transactivation potential. The inhibitory effect of p53 on beta-catenin is apparently mediated by the ubiquitin-proteasome system and requires an active glycogen synthase kinase 3beta (GSK3beta). Mutations in the N terminus of beta-catenin which compromise its degradation by the proteasomes, overexpression of dominant-negative DeltaF-beta-TrCP, or inhibition of GSKbeta activity all rendered beta-catenin resistant to down-regulation by p53. These findings support the notion that there will be a selective pressure for the loss of wild-type p53 expression in cancers that are driven by excessive accumulation of beta-catenin.