THE ZINC-FINGER PROTEIN SLUG CAUSES DESMOSOME DISSOCIATION, AN INITIAL AND NECESSARY STEP FOR GROWTH FACTOR-INDUCED EPITHELIAL-MESENCHYMAL TRANSITION

Epithelial-mesenchymal transition (EMT) is an essential morphogenetic process during embryonic development. It can be induced in vitro by he patocyte 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 increase d transiently in FGF-1-treated NBT-II cells. Transient or stable trans fection of Slug cDNA in NBT-II cells resulted in a striking disappeara nce of the desmosomal markers desmoplakin and desmoglein from cell-cel l contact areas, mimicking the initial steps of FGF-1 or HGF/SF-induce d 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 an tisense Slug cDNA were able to resist EMT induction by FGF-1 or even H GF/SF. This antisense effect was suppressed by retransfection with Slu g sense cDNA. Our results indicate that Slug induces the first phase o f growth factor-induced EMT, including desmosome dissociation, cell sp reading, and initiation of cell separation. Moreover, the antisense in hibition experiments suggest that Slug is also necessary for EMT.