Regulation of β-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 NH2-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.