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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.

Pubmed ID: 11050151

Authors

  • Sun Y
  • Kolligs FT
  • Hottiger MO
  • Mosavin R
  • Fearon ER
  • Nabel GJ

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

November 7, 2000

Associated Grants

None

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