Regulation of β-catenin transformation by the p300 transcriptional coactivator

Yongnian Sun, Frank T. Kolligs, Michael O. Hottiger, Rashid Mosavin, Eric R. Fearon, Gary J. Nabel

Research output: Contribution to journalArticle

Abstract

The β-catenin protein plays a critical role in embryonic development and mature tissue homeostasis through its effects on Ecadherin-mediated cell adhesion and Wnt-dependent signal transduction. In colon and other cancers, mutations of β-catenin or the adenomatous polyposis coli (APC) tumor suppressor appear to stabilize β-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 β-catenin's interactions with TCF/Lef proteins contribute to neoplastic transformation is lacking. We report that the transcriptional coactivator p300 interacts with β-catenin in vitro and in vivo and is critical for β-catenin-mediated neoplastic transformation. p300 synergistically activates β-catenin/TCF transcription, and their biochemical association requires the CH1 domain of p300 and a region of β-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 β-catenin-transformed rat epithelial cell line and a human colon carcinoma line with a β-catenin mutation. These findings demonstrate a critical role for p300 in β-catenin/TCF transcription and in cancers arising from defects in β-catenin regulation.

Original languageEnglish (US)
Pages (from-to)12613-12618
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number23
DOIs
StatePublished - Nov 7 2000
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • General

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