Regulation of beta -catenin transformation by the p300 transcriptional coactivator.
The beta-catenin protein plays a critical role in embryonic development and mature tissue homeostasis through its effects on E-cadherin-mediated cell adhesion and Wnt-dependent signal transduction. In colon and other cancers, mutations of beta-catenin or the adenomatous polyposis coli (APC) tumor suppressor appear to stabilize beta-catenin and enhance its interaction with ... T cell factor (TCF) or lymphoid enhancer factor (Lef) transcription factors. At present, a complete picture of the means by which beta-catenin's interactions with TCF/Lef proteins contribute to neoplastic transformation is lacking. We report that the transcriptional coactivator p300 interacts with beta-catenin in vitro and in vivo and is critical for beta-catenin-mediated neoplastic transformation. p300 synergistically activates beta-catenin/TCF transcription, and their biochemical association requires the CH1 domain of p300 and a region of beta-catenin that includes its NH(2)-terminal transactivation domain and the first two armadillo repeats. Lowering of cellular p300 levels by using a ribozyme directed against p300 reduced TCF transcriptional activity and inhibited the neoplastic growth properties of a beta-catenin-transformed rat epithelial cell line and a human colon carcinoma line with a beta-catenin mutation. These findings demonstrate a critical role for p300 in beta-catenin/TCF transcription and in cancers arising from defects in beta-catenin regulation.
Mesh Terms:
Animals, Cell Line, Cell Transformation, Neoplastic, Cytoskeletal Proteins, DNA-Binding Proteins, E1A-Associated p300 Protein, Gene Expression Regulation, Humans, Jurkat Cells, Lymphoid Enhancer-Binding Factor 1, Mice, Nuclear Proteins, Recombinant Fusion Proteins, Trans-Activators, Transcription Factors, Transcription, Genetic, Tumor Cells, Cultured, beta Catenin
Animals, Cell Line, Cell Transformation, Neoplastic, Cytoskeletal Proteins, DNA-Binding Proteins, E1A-Associated p300 Protein, Gene Expression Regulation, Humans, Jurkat Cells, Lymphoid Enhancer-Binding Factor 1, Mice, Nuclear Proteins, Recombinant Fusion Proteins, Trans-Activators, Transcription Factors, Transcription, Genetic, Tumor Cells, Cultured, beta Catenin
Proc. Natl. Acad. Sci. U.S.A.
Date: Nov. 07, 2000
PubMed ID: 11050151
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