DIRECT EVIDENCE FOR A ROLE OF β-CATENIN/LEF-1 SIGNALING PATHWAY IN INDUCTION OF EMT

Authors

  • Kwonseop Kim,

    1. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, U.S.A.
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    • Dr Kwonseop Kim, College of Pharmacy, Chonnam National University, 300 Yongbong-dong, GwangJu (500-757), South Korea.

  • Zifan Lu,

    1. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, U.S.A.
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  • Elizabeth D. Hay

    Corresponding author
    1. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, U.S.A.
      To whom correspondence should be addressed: Dr Elizabeth D. Hay, Department of Cell Biology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, U.S.A. Tel: 1-617-432-1651; Fax: 1-617-432-0407; Email: ehay@hms.harvard.edu
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To whom correspondence should be addressed: Dr Elizabeth D. Hay, Department of Cell Biology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, U.S.A. Tel: 1-617-432-1651; Fax: 1-617-432-0407; Email: ehay@hms.harvard.edu

Abstract

Epithelial-mesenchymal transformation (EMT) is an important process in development that is characterized by loss of E-cadherin, β-catenin relocalization, and acquisition of elongated cell shape and ability to invade ECM. β-catenin has been shown to activate LEF-1 transcription during EMT induced in vitro by c-Fos. Here, we ask whether or not LEF-1 directly introduced into epithelial cells in an adenovirus construct can induce EMT. In normal epithelial cell lines, such as HCE and MDCK cells, that contain functional APC, nuclear β-catenin induced by exogenous LEF-1 is rapidly exported and EMT is not induced. Leptomycin-B blocks β-catenin nuclear export, but no EMT occurs due to toxicity. Addition of Wnt-1 to normal epithelial cell lines stabilizes cytoplasmic β-catenin that LEF-1 then transports to nuclei, causing a small amount of EMT. Our experiments demonstrated, however, that overexpressed LEF-1 upregulates nuclear β-catenin and promotes dramatic EMT in DLD-1 epithelial tumors that retain nuclear β-catenin. This EMT is reversible if the LEF-1 virus is removed. Thus, our results demonstrate that LEF-1 can induce EMT directly when its transcription activity is activated by stable nuclear β-catenin. Normal adult epithelial cells appear to use APC to keep β-catenin out of the nucleus, thereby avoiding pathologies such as metastases due to LEF/β-catenin-induced EMT.

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