title: Characterization of E-cadherin-dependent and -independent events in a new model of c-Fos-mediated epithelial-mesenchymal transition.
abstract: Fos proteins have been implicated in control of tumorigenesis-related genetic programs including invasion, angiogenesis, cell proliferation and apoptosis. In this study, we demonstrate that c-Fos is able to induce mesenchymal transition in murine tumorigenic epithelial cell lines. Expression of c-Fos in MT1TC1 cells led to prominent alterations in cell morphology, increased expression of mesenchymal markers, vimentin and S100A4, DNA methylation-dependent down-regulation of E-cadherin and abrogation of cell-cell adhesion. In addition, c-Fos induced a strong beta-catenin-independent proliferative response in MT1TC1 cells and stimulated cell motility, invasion and adhesion to different extracellular matrix proteins. To explore whether loss of E-cadherin plays a role in c-Fos-mediated mesenchymal transition, we expressed wild-type E-cadherin and two different E-cadherin mutants in MT1TC1/c-fos cells. Expression of wild-type E-cadherin restored epithelioid morphology and enhanced cellular levels of catenins. However, exogenous E-cadherin did not influence expression of c-Fos-dependent genes, only partly suppressed growth of MT1TC1/c-fos cells and produced no effect on c-Fos-stimulated cell motility and invasion in matrigel. On the other hand, re-expression of E-cadherin specifically negated c-Fos-induced adhesion to collagen type I, but not to laminin or fibronectin. Of interest, mutant E-cadherin which lacks the ability to form functional adhesive complexes had an opposite, potentiating effect on cell adhesion to collagen I. These data suggest that cell adhesion to collagen I is regulated by the functional state of E-cadherin. Overall, our data demonstrate that, with the exception of adhesion to collagen I, c-Fos is dominant over E-cadherin in relation to the aspects of mesenchymal transition assayed in this study.
authors.affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, Hodgkin Bldg., Lancaster Rd, LE1 9HN, Leicester, UK.
authors.forename: Jakob
authors.initials: J
authors.lastname: Mejlvang
authors.forename: Marina
authors.initials: M
authors.lastname: Kriajevska
authors.forename: Fedor
authors.initials: F
authors.lastname: Berditchevski
authors.forename: Igor
authors.initials: I
authors.lastname: Bronstein
authors.forename: Eugene M
authors.initials: EM
authors.lastname: Lukanidin
authors.forename: J Howard
authors.initials: JH
authors.lastname: Pringle
authors.forename: J Kilian
authors.initials: JK
authors.lastname: Mellon
authors.forename: Eugene M
authors.initials: EM
authors.lastname: Tulchinsky
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000818:Animals; D015820:Cadherins / Q000235:genetics*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; D016760:Proto-Oncogene Proteins c-fos; D051176:beta Catenin