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

Abstract

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.

The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it

“…Desmosomes (circles, Fig. 12) disappear during palatal EMT, as reported for Slug-induced EMT elsewhere (Savagner et al, 1997).…”

“…Epithelia under tension develop very strong adherens junctions called desmosomes (macula adherens, Fig. 1B) that contain specialized cadherins and catenins that dissociate during EMT (Savagner et al, 1997). Specialized cadherins (Takeichi, 1995) are also found in endothelium (VE-cadherin) and fibroblasts (N-cadherin).…”

Protein tyrosine phosphatase ε increases the risk of mammary hyperplasia and mammary tumors in transgenic mice

“…This process, termed EMT (epithelial-to-mesenchymal transition), has been documented in well-advanced epithelial tumors and is correlated with increases in metastatic potential (reviewed in Birchmeier et al, 1996). EMT of mammary epithelial cells can be caused by several factors, among them expression of growth factors (Miettinen et al, 1994;Solic and Davies, 1997), transcription factors (Gilles et al, 1997;Savagner et al, 1997), or matrix metallo-proteases (Lochter et al, 1997;Ahmad et al, 1998).…”

Evidence for a function of CtBP in epithelial gene regulation and anoikis

“…In this light, expression of the Drosophila ZEB homologue, zfh-1, is controlled by members of the snail family of transcription factors (Kosman et al, 1996); Snail has been proposed as an alternative E-cadherin repressor (Batlle et al, 2000;Cano et al, 2000) (although its repression activity appears to be non-speci®c in our preliminary experiments; data not shown). Another human member of this family, slug, causes epithelial to mesenchymal transitions when overexpressed (Savagner et al, 1997). In any event, the E-box mediated repression of E-cadherin seen in spontaneous human tumors or in response to ras (Frisch, unpublished results) or HER2/cerbB2 (D'souza and Taylor-Papadimitriou, 1994) oncogenes may in some cases involve the regulation of dEF1/ ZEB-CtBP complexes.…”