Direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT

Cell Biol Int. 2002;26(5):463-76. doi: 10.1006/cbir.2002.0901.

Abstract

Epithelial-mesenchymal transformation (EMT) is an important process in development that is characterized by loss of E-cadherin, beta-catenin relocalization, and acquisition of elongated cell shape and ability to invade ECM. beta-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 beta-catenin induced by exogenous LEF-1 is rapidly exported and EMT is not induced. Leptomycin-B blocks beta-catenin nuclear export, but no EMT occurs due to toxicity. Addition of Wnt-1 to normal epithelial cell lines stabilizes cytoplasmic beta-catenin that LEF-1 then transports to nuclei, causing a small amount of EMT. Our experiments demonstrated, however, that overexpressed LEF-1 upregulates nuclear beta-catenin and promotes dramatic EMT in DLD-1 epithelial tumors that retain nuclear beta-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 beta-catenin. Normal adult epithelial cells appear to use APC to keep beta-catenin out of the nucleus, thereby avoiding pathologies such as metastases due to LEF/beta-catenin-induced EMT.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Active Transport, Cell Nucleus
  • Adenoviridae
  • Animals
  • Cell Communication
  • Cell Line
  • Cell Nucleus / metabolism
  • Cytoskeletal Proteins / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Desmoplakins
  • Dogs
  • Epithelial Cells / physiology
  • Genetic Vectors
  • Humans
  • Karyopherins / metabolism
  • Lymphoid Enhancer-Binding Factor 1
  • Mesoderm / physiology
  • Mice
  • Receptors, Cytoplasmic and Nuclear*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction*
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Desmoplakins
  • Karyopherins
  • LEF1 protein, human
  • Lef1 protein, mouse
  • Lymphoid Enhancer-Binding Factor 1
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Fusion Proteins
  • Trans-Activators
  • Transcription Factors
  • beta Catenin
  • exportin 1 protein