Snail and Slug promote epithelial-mesenchymal transition through beta-catenin-T-cell factor-4-dependent expression of transforming growth factor-beta3.
Members of the Snail family of transcription factors have been shown to induce epithelial-mesenchymal transition (EMT), a fundamental mechanism of embryogenesis and progressive disease. Here, we show that Snail and Slug promote formation of beta-catenin-T-cell factor (TCF)-4 transcription complexes that bind to the promoter of the TGF-beta3 gene to increase its transcription. Subsequent transforming growth factor (TGF)-beta3 signaling increases LEF-1 gene expression causing formation of beta-catenin-lymphoid enhancer factor (LEF)-1 complexes that initiate EMT. TGF-beta1 or TGF-beta2 stimulates this signaling mechanism by up-regulating synthesis of Snail and Slug. TGF-beta1- and TGF-beta2-induced EMT were found to be TGF-beta3 dependent, establishing essential roles for multiple TGF-beta isoforms. Finally, we determined that beta-catenin-LEF-1 complexes can promote EMT without upstream signaling pathways. These findings provide evidence for a unified signaling mechanism driven by convergence of multiple TGF-beta and TCF signaling molecules that confers loss of cell-cell adhesion and acquisition of the mesenchymal phenotype.
Medici
Damian
D
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Hay
Elizabeth D
ED
Olsen
Bjorn R
BR
D000818:Animals; D002460:Cell Line; D004285:Dogs; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071250:Snail Family Transcription Factors; D051820:TCF Transcription Factors / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D053781:Transforming Growth Factor beta2 / Q000494:pharmacology; D053782:Transforming Growth Factor beta3 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
D051821:Lymphoid Enhancer-Binding Factor 1; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D051176:beta Catenin
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