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 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.
Sadot
E
E
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Geiger
B
B
Oren
M
M
Ben-Ze'ev
A
A
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000235:genetics; D003599:Cytoskeleton / Q000378:metabolism; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005799:Genes, Dominant; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D013997:Time Factors; D015534:Trans-Activators; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D009097:Multienzyme Complexes; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; D051176:beta Catenin; D004317:Doxorubicin; D008156:Luciferases; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D002945:Cisplatin