Cooperation between snail and LEF-1 transcription factors is essential for TGF-beta1-induced epithelial-mesenchymal transition.
Transforming growth factor beta 1 (TGF-beta1) has been shown to induce epithelial-mesenchymal transition (EMT) during various stages of embryogenesis and progressive disease. This alteration in cellular morphology is typically characterized by changes in cell polarity and loss of adhesion proteins such as E-cadherin. Here we demonstrate that EMT is associated with loss of claudin-1, claudin-2, occludin, and E-cadherin expression within 72 h of exposure to TGF-beta1 in MDCKII cells. It has been suggested that this expression loss occurs through TGF-beta1 in a Smad-independent mechanism, involving MEK and PI3K pathways, which have previously been shown to induce expression of the Snail (SNAI-1) gene. Here we show that these pathways are responsible for loss of tight junctions and a partial loss of E-cadherin. However, our results also demonstrate that a complete loss of E-cadherin and transformation to the mesenchymal phenotype are dependent on Smad signaling, which subsequently stimulates formation of beta-catenin/LEF-1 complexes that induce EMT.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Damian
D
Medici
Elizabeth D
ED
Hay
Daniel A
DA
Goodenough
D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004285:Dogs; D047108:Embryonic Development; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency*; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D019108:Tight Junctions / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D051176:beta Catenin / Q000378:metabolism*
D015820:Cadherins; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins; D051785:Smad Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D020930:MAP Kinase Kinase Kinases