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SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions.

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journal contribution
posted on 24.10.2012, 09:00 by C. Vandewalle, J. Comijn, De Craene B., P. Vermassen, E. Bruyneel, H. Andersen, Eugene Tulchinsky, Van Roy F., G. Berx
SIP1/ZEB2 is a member of the deltaEF-1 family of two-handed zinc finger nuclear factors. The expression of these transcription factors is associated with epithelial mesenchymal transitions (EMT) during development. SIP1 is also expressed in some breast cancer cell lines and was detected in intestinal gastric carcinomas, where its expression is inversely correlated with that of E-cadherin. Here, we show that expression of SIP1 in human epithelial cells results in a clear morphological change from an epithelial to a mesenchymal phenotype. Induction of this epithelial dedifferentiation was accompanied by repression of several cell junctional proteins, with concomitant repression of their mRNA levels. Besides E-cadherin, other genes coding for crucial proteins of tight junctions, desmosomes and gap junctions were found to be transcriptionally regulated by the transcriptional repressor SIP1. Moreover, study of the promoter regions of selected genes by luciferase reporter assays and chromatin immunoprecipitation shows that repression is directly mediated by SIP1. These data indicate that, during epithelial dedifferentiation, SIP1 represses in a coordinated manner the transcription of genes coding for junctional proteins contributing to the dedifferentiated state; this repression occurs by a general mechanism mediated by Smad Interacting Protein 1 (SIP1)-binding sites.

Funding

J.C. was supported by the ‘Vlaams Instituut voor de Bevordering van het Wetenschappelijk-Technologisch Onderzoek in de industrie’ en the ‘Stichting Emmanuel Van der Schueren’. C.V. is a research assistant with the Fund for Scientific Research, Flanders (FWO). G.B. is a postdoctoral fellow with the FWO. The research was supported by the Association for International Cancer Research (AICR-UK), the Geconcerteerde Onderzoeksacties of Ghent University, FWO-Flanders, Fortis Insurances (Belgium), and Interuniversity Attraction Poles Programme (IUAP, Belgian Science Policy). Funding to pay the Open Access publication charges for this article was provided by IUAP

History

Citation

Nucleic Acids Research, 2005, 33 (20), pp. 6566-6578

Published in

Nucleic Acids Research

Publisher

Oxford University Press (OUP)

issn

0305-1048

eissn

1362-4962

Copyright date

2005

Available date

24/10/2012

Publisher version

http://nar.oxfordjournals.org/content/33/20/6566

Language

eng