Down-Regulation of β-Catenin by Activated p53

Abstract

β-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 β-catenin in the nucleus, where it activates the transcription of target genes. Abnormal accumulation of β-catenin is characteristic of various types of cancer and is caused by mutations either in the adenomatous polyposis coli protein, which regulates β-catenin degradation, or in the β-catenin molecule itself. Aberrant accumulation of β-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 β-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 β-catenin level was accompanied by inhibition of its transactivation potential. The inhibitory effect of p53 on β-catenin is apparently mediated by the ubiquitin-proteasome system and requires an active glycogen synthase kinase 3β (GSK3β). Mutations in the N terminus of β-catenin which compromise its degradation by the proteasomes, overexpression of dominant-negative ΔF-β-TrCP, or inhibition of GSKβ activity all rendered β-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 β-catenin.

ACKNOWLEDGMENTS

This study was supported by grants from the German-Israeli Foundation for Scientific Research and Development, the Cooperation Program in Cancer Research between the German Cancer Research Center (DKFZ) and the Israeli Ministry of Science and Arts (IMOSA), CaP CURE, The Israel Science Foundation, The Crown Endowment Fund for Immunological Research, The M. D. Moross Institute for Cancer Research, NIH (grant RO1 CA-40099), and the German-Israel Project Cooperation (DIP). B.G. holds the E. Neter Chair of Cell and Tumor Biology, and A.B.-Z. holds the Lunenfeld-Kunin Chair in Genetics and Cell Biology.

We thank G. Del Sal and J. Zhurinsky for illuminating discussions.