Downregulation of beta-catenin by p53 involves changes in the rate of beta-catenin phosphorylation and Axin dynamics.
beta-Catenin, a structural component of cell-cell adhesions, is also a potent signaling molecule in the Wnt pathway activating target genes together with Lef/Tcf transcription factors. In colorectal and many other types of cancer, beta-catenin is hyperactive owing to mutations in beta-catenin, or in components regulating beta-catenin degradation. Deregulated beta-catenin can cause the activation of p53, a key tumor suppressor mutated in most cancers. Activated p53 can feed back and downregulate beta-catenin. Here we investigated the mechanisms involved in downregulation of beta-catenin by p53. We found that the p53-mediated reduction in beta-catenin involves enhanced phosphorylation of beta-catenin on key NH(2)-terminal serines and requires CK1 and GSK-3beta activities, both being components of the beta-catenin degradation machinery. Mutations in these NH(2)-terminal beta-catenin serines blocked the ability of p53 to enhance the turnover of beta-catenin. p53 also induced a shift in the distribution of the scaffold molecule Axin to a Triton X-100-soluble fraction, and led to depletion of beta-catenin from this Triton-soluble fraction. The majority of Axin and phosphorylated beta-catenin, however, colocalized in Triton X-100-insoluble punctate aggregates near the plasma membrane, and kinetics studies indicated that in the presence of p53 the movement of Axin into and out of the Triton X-100-insoluble fraction is accelerated. These results suggest that p53 induces a faster mobilization of Axin into the degradation complex thereby enhancing beta-catenin turnover as part of a protective mechanism against the development of cancer.
Levina
Elina
E
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Oren
Moshe
M
Ben-Ze'ev
Avri
A
D060466:Axin Protein; D047388:Casein Kinases; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D003902:Detergents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D016158:Genes, p53; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D046911:Macromolecular Substances; D009363:Neoplasm Proteins / Q000378:metabolism; D017830:Octoxynol / Q000494:pharmacology; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011494:Protein Kinases / Q000502:physiology; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012995:Solubility; D013347:Subcellular Fractions / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D051176:beta Catenin
D060466:Axin Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D003902:Detergents; D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D010768:Phosphoserine; D017830:Octoxynol; D011494:Protein Kinases; D047388:Casein Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride