The Zinc-Finger Protein Slug Causes Desmosome Dissociation, an Initial and Necessary Step for Growth Factor-Induced Epithelial-Mesenchymal Transition

• Published in: The Journal of cell biology 1997-06, Vol.137 (6), p.1403-1419
• Main Authors: Savagner, Pierre, Yamada, Kenneth M., Thiery, Jean Paul
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Cadherins - metabolism; Cell adhesion; Cell lines; Cell Movement; Cells; Cellular biology; Chickens; Cloning, Molecular; Complementary DNA; Desmoplakins; Desmosomes; Desmosomes - drug effects; Desmosomes - physiology; DNA, Antisense; DNA, Complementary; Epithelial cells; Epithelium - drug effects; Fibroblast Growth Factor 1 - pharmacology; Gene Expression; Hepatocyte Growth Factor - pharmacology; Hepatocytes; Humans; Keratins; Keratins - metabolism; Mammals; Mesoderm - physiology; Mice; Microscopy, Fluorescence; Molecular Sequence Data; Phenotype; Proteins; Rats; RNA, Messenger; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Slugs; Snail Family Transcription Factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection; Tumor Cells, Cultured; Zinc Fingers
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.137.6.1403

Epithelial-mesenchymal transition (EMT) is an essential morphogenetic process during embryonic development. It can be induced in vitro by hepatocyte growth factor/scatter factor (HGF/SF), or by FGF-1 in our NBT-II cell model for EMT. We tested for a central role in EMT of a zinc-finger protein called Slug. Slug mRNA and protein levels were increased transiently in FGF-1-treated NBT-II cells. Transient or stable transfection of Slug cDNA in NBT-II cells resulted in a striking disappearance of the desmosomal markers desmoplakin and desmoglein from cell-cell contact areas, mimicking the initial steps of FGF-1 or HGF/SF-induced EMT. Stable transfectant cells expressed Slug protein and were less epithelial, with increased cell spreading and cell-cell separation in subconfluent cultures. Interestingly, NBT-II cells transfected with antisense Slug cDNA were able to resist EMT induction by FGF-1 or even HGF/SF. This antisense effect was suppressed by retransfection with Slug sense cDNA. Our results indicate that Slug induces the first phase of growth factor-induced EMT, including desmosome dissociation, cell spreading, and initiation of cell separation. Moreover, the antisense inhibition experiments suggest that Slug is also necessary for EMT.