title: SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions.
abstract: 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.
authors.affiliation: Unit of Molecular and Cellular Oncology, Department for Molecular Biomedical Research, VIB-Ghent University, Belgium.
authors.forename: Cindy
authors.initials: C
authors.lastname: Vandewalle
authors.forename: Joke
authors.initials: J
authors.lastname: Comijn
authors.forename: Bram
authors.initials: B
authors.lastname: De Craene
authors.forename: Petra
authors.initials: P
authors.lastname: Vermassen
authors.forename: Erik
authors.initials: E
authors.lastname: Bruyneel
authors.forename: Henriette
authors.initials: H
authors.lastname: Andersen
authors.forename: Eugene
authors.initials: E
authors.lastname: Tulchinsky
authors.forename: Frans
authors.initials: F
authors.lastname: Van Roy
authors.forename: Geert
authors.initials: G
authors.lastname: Berx
mesh_terms: D001665:Binding Sites; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology; D009154:Mutation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology*
chemical_list: D015820:Cadherins; D002843:Chromatin; D017630:Connexins; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins