Regulation of beta -catenin transformation by the p300 transcriptional coactivator.

Abstract

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.

• Authors: Y Sun, F T Kolligs, M O Hottiger, R Mosavin, E R Fearon, G J Nabel
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 97 Issue 23 Pg. 12613-8 (Nov 07 2000) ISSN: 0027-8424 [Print] United States
• PMID: 11050151 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CTNNB1 protein, human
• CTNNB1 protein, mouse
• Cytoskeletal Proteins
• DNA-Binding Proteins
• Lymphoid Enhancer-Binding Factor 1
• Nuclear Proteins
• Recombinant Fusion Proteins
• Trans-Activators
• Transcription Factors
• beta Catenin
• E1A-Associated p300 Protein
• Ep300 protein, mouse

Topics

• Animals
• Cell Line
• Cell Transformation, Neoplastic
• Cytoskeletal Proteins (genetics, metabolism)
• DNA-Binding Proteins (genetics)
• E1A-Associated p300 Protein
• Gene Expression Regulation
• Humans
• Jurkat Cells
• Lymphoid Enhancer-Binding Factor 1
• Mice
• Nuclear Proteins (genetics, metabolism, physiology)
• Recombinant Fusion Proteins (genetics, metabolism, physiology)
• Trans-Activators (genetics, metabolism, physiology)
• Transcription Factors (genetics)
• Transcription, Genetic
• Tumor Cells, Cultured
• beta Catenin