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.
Mesh Terms:
Animals, Cell Line, Dogs, Epithelium, Humans, Lymphoid Enhancer-Binding Factor 1, Mesoderm, Signal Transduction, Snail Family Transcription Factors, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, Transcription Factors, Transcription, Genetic, Transforming Growth Factor beta1, Transforming Growth Factor beta2, Transforming Growth Factor beta3, Up-Regulation, beta Catenin
Mol Biol Cell
Date: Nov. 01, 2008
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