Down-regulation of beta-catenin by activated p53

beta -Catenin is a cytoplasmic protein that participates in the assembly of cell-cell adherens junctions by binding cadherins to the actin cytoskeleto n. In addition, it is a key component of the Wnt signaling pathway. Activat ion of this pathway triggers the accumulation of beta -catenin in the nucle us, where it activates the transcription of target genes. Abnormal accumula tion of beta -catenin is characteristic of various types of cancer and is c aused by mutations either in the adenomatous polyposis coli protein, which regulates beta -catenin degradation, or in the beta -catenin molecule itsel f. Aberrant accumulation of beta -catenin in tumors is often associated wit h mutational inactivation of the p53 tumor suppressor. Here we show that ov erexpression of wild-type p53, by either transfection or DNA damage, down-r egulates beta -catenin in human and mouse cells. This effect was not obtain ed with transcriptionally inactive p53, including a common tumor-associated p53 mutant. The reduction in beta -catenin level was accompanied by inhibi tion of its transactivation potential. The inhibitory effect of p53 on beta -catenin is apparently mediated by the ubiquitin-proteasome system and req uires an active glycogen synthase kinase 3 beta (GSK3 beta). Mutations in t he N terminus of beta -catenin which compromise its degradation by the prot easomes, overexpression of dominant-negative DeltaF-beta -TrCP, or inhibiti on of GSK beta activity all rendered beta -catenin resistant to down-regula tion by p53. These findings support the notion that there will be a selecti ve pressure for the loss of wild-type p53 expression in cancers that are dr iven by excessive accumulation of beta -catenin.