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

doi:10.1083/jcb.137.6.1403

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© The Rockefeller University Press, 0021-9525/1997//1403 $5.00
The Journal of Cell Biology, Volume 137, Number 6, , 1997 1403-1419

Article

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

Pierre Savagner^*^,, Kenneth M. Yamada, and Jean Paul Thiery^*

^* Centre National de la Recherche Scientifique–Institut Curie, 75231 Paris Cedex 05, France; and Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892-4370

Epithelial–mesenchymal transition (EMT) is an essentialmorphogenetic process during embryonic development. It can beinduced in vitro by hepatocyte growth factor/scatter factor(HGF/SF), or by FGF-1 in our NBT-II cell model for EMT. Wetested for a central role in EMT of a zinc-finger protein calledSlug. Slug mRNA and protein levels were increased transientlyin FGF-1–treated NBT-II cells. Transient or stable transfectionof Slug cDNA in NBT-II cells resulted in a striking disappearanceof the desmosomal markers desmoplakin and desmoglein from cell–cellcontact areas, mimicking the initial steps of FGF-1 or HGF/SF-induced EMT. Stable transfectant cells expressed Slug proteinand were less epithelial, with increased cell spreading andcell–cell separation in subconfluent cultures. Interestingly,NBT-II cells transfected with antisense Slug cDNA were ableto resist EMT induction by FGF-1 or even HGF/SF. This antisenseeffect 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 alsonecessary for EMT.

1. Abbreviations used in this paper: EMT, epithelial-mesenchymaltransition; HGF/SF, hepatocyte growth factor/scatter factor;IL-2R, interleukin-2 receptor; MDCK, Madin-Darby canine kidney.

We are most grateful to Yoshihiko Yamada (National Instituteof Dental Research) for the help with cloning of mouse slug.We acknowledge the expert technical assistance of Bill Swain(National Institute of Dental Research) for the electron microscopy.The manuscript was improved by critical reading by BrigitteBoyer, Jacqueline Jouanneau, and Ana-Maria Vallés (InstitutCurie).

Address all correspondence to Pierre Savagner, CraniofacialDevelopmental Biology and Regeneration Branch, NIDR, Bldg. 30,Rm. 424, 30 Convent Drive MSC 4370, National Institutes ofHealth, Bethesda, MD 20892-4370. Tel: (301) 496-6040; Fax:(301) 402-0897.

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