Activator protein 2α associates with adenomatous polyposis coli/β-catenin and inhibits β-catenin/T-cell factor transcriptional activity in colorectal cancer cells

Qingjie Li, Roderick H. Dashwood

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

In most human colorectal cancers, mutations in the adenomatous polyposis coli gene (APC) or CTNNB1 constitutively activate the β-catenin/T-cell factor (TCF)/lymphoid enhancer factor (LEF) signaling pathway. Here, we show that the transcription factor activator protein (AP)-2α inhibited a β-catenin/TCF-responsive reporter in human embryonic kidney 293 cells and in two human colorectal cancer lines, despite the fact that β3-catenin and TCF-4 protein levels were unchanged in the nucleus. Co-immunoprecipitation studies revealed that AP-2α formed a complex with APC and β-catenin and that AP-2α disrupted β-catenin/TCF-4 interactions in the nucleus. Thus, AP-2α·APC·β-catenin complex formation appears to suppress β-catenin transactivation by shifting the pool of nuclear β-catenin toward an inactive form, having reduced binding to TCF/LEF transcription factors. Glutathione S-transferase pull-down assays showed that AP-2α physically associated with APC rather than with β-catenin, and the AP-2α binding site was identified in the N terminus of APC, involving both the heptad and armadillo repeat domains, whereas the APC binding site in AP-2α was in the basic region of the C-terminal DNA binding domain. These findings provide the first evidence for a specific interaction between the tumor suppressor protein APC and the transcription factor AP-2α, and they suggest a link between the Wnt signaling pathway and various other pathways of development and differentiation associated with AP-2α.

Original languageEnglish (US)
Pages (from-to)45669-45675
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number44
DOIs
StatePublished - Oct 29 2004
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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