Deregulated beta-catenin induces a p53- and ARF-dependent growth arrest and cooperates with Ras in transformation.
Aberrant activation of beta-catenin contributes to the onset of a variety of tumors. We report that a tumor-derived beta-catenin mutant induces accumulation and activation of the p53 tumor suppressor protein. Induction is mediated through ARF, an alternative reading frame product of the INK4A tumor suppressor locus, in a manner partially dependent on the transcription factor E2F1. In wild-type mouse embryo fibroblasts, mutant beta-catenin inhibits cell proliferation and imposes a senescence-like phenotype. This does not occur in cells lacking either ARF or p53, where deregulated beta-catenin actually overrides density-dependent growth inhibition and cooperates with activated Ras in transformation. Thus, the oncogenic activity of deregulated beta-catenin is curtailed by concurrent activation of the p53 pathway, thereby providing a protective mechanism against cancer. When the p53 pathway is impaired, deregulated beta-catenin is free to manifest its oncogenic features. This can occur not only by p53 mutations, but also by ablation of ARF expression, as observed frequently in early stages of colorectal carcinogenesis.
Damalas
A
A
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Kahan
S
S
Shtutman
M
M
Ben-Ze'ev
A
A
Oren
M
M
D020727:ADP-Ribosylation Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D011905:Genes, ras; D008156:Luciferases / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D011994:Recombinant Proteins / Q000032:analysis; D015534:Trans-Activators; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D008156:Luciferases; D020727:ADP-Ribosylation Factors