Activation of AXIN2 expression by β-catenin-T cell factor: A feedback repressor pathway regulating Wnt signaling

Janet Y. Leung, Frank T. Kolligs, Rong Wu, Yali Zhai, Rork Kuick, Samir Hanash, Kathleen R. Cho, Eric R. Fearon

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Abstract

The Wnt pathway regulates cell fate, proliferation, and apoptosis, and defects in the pathway play a key role in many cancers. Although Wnts act to stabilize β-catenin levels in the cytosol and nucleus, a multiprotein complex containing adenomatous polyposis coli, glycogen synthase kinase 3β, and Axin1 or its homolog Axin2/Axi1/conductin promotes β-catenin phosphorylation and subsequent proteasomal degradation. We found that the rat Axil gene was strongly induced upon neoplastic transformation of RK3E cells by mutant β-catenin or γ-catenin or after ligand-induced activation of a β-catenin-estrogen receptor fusion protein. Expression of Wntl in murine breast epithelial cells activated the conductin gene, and human cancers with defective β-catenin regulation had elevated AXIN2 gene and protein expression. Expression of AXIN2/Axil was strongly repressed in cancer cells by restoration of wild type adenomatous polyposis coli function or expression of a dominant negative form of T cell factor (TCF)-4. TCF binding sites in the AXIN2 promoter played a key role in the ability of β-catenin to activate AXIN2 transcription. In contrast to AXIN2/Axil, expression of human or rat Axin1 homologs was nominally affected by β-catenin-TCF. Because Axin2 can inhibit β-catenin abundance and function, the data implicate AXIN2 in a negative feedback pathway regulating Wnt signaling. Additionally, although Axin1 and Axin2 have been thought to have comparable functions, the observation that Wnt pathway activation elevates AXIN2 but not AXIN1 expression suggests that there may be potentially significant functional differences between the two proteins.

Original languageEnglish (US)
Pages (from-to)21657-21665
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number24
DOIs
StatePublished - Jun 14 2002

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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