Peinado, HectorQuintanilla, MiguelCano, Amparo2024-02-122024-02-122003-06-06J Biol Chem . 2003 ;278(23):21113-23.0021-9258http://hdl.handle.net/20.500.12105/17963We thank A. Ben-Ze’ev, H. Clevers, T. Gridley, J. Massague´, P. Rodriguez-Viciana, and M. Takeichi for providing vectors, genomic clones, and antibodies and M. A. Nieto and M. C. Iglesias for helpful suggestions and critical reading of the manuscript.The Snail transcription factor has been described recently as a strong repressor of E-cadherin in epithelial cell lines, where its stable expression leads to the loss of E-cadherin expression and induces epithelial-mesenchymal transitions and an invasive phenotype. The mechanisms regulating Snail expression in development and tumor progression are not yet known. We show here that transforming growth factor beta-1 (TGFbeta1) induces Snail expression in Madin-Darby canine kidney cells and triggers epithelial-mesenchymal transitions by a mechanism dependent on the MAPK signaling pathway. Furthermore, TGFbeta1 induces the activity of Snail promoter, whereas fibroblast growth factor-2 has a milder effect but cooperates with TGFbeta1 in the induction of Snail promoter. Interestingly, TGFbeta1-mediated induction of Snail promoter is blocked by a dominant negative form of H-Ras (N17Ras), whereas oncogenic H-Ras (V12Ras) induces Snail promoter activity and synergistically cooperates with TGFbeta1. The effects of TGFbeta1 on Snail promoter are dependent of MEK1/2 activity but are apparently independent of Smad4 activity. In addition, H-Ras-mediated induction of Snail promoter, alone or in the presence of TGFbeta1, depends on both MAPK and phosphatidylinositol 3-kinase activities. These data support that MAPK and phosphatidylinositol 3-kinase signaling pathways are implicated in TGFbeta1-mediated induction of Snail promoter, probably through Ras activation and its downstream effectors.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/AnimalsCadherinsCell LineCell MovementDNA-Binding ProteinsDogsEpithelial CellsFibroblast Growth Factor 2Gene ExpressionGenes, rasKidneyMAP Kinase Kinase 1MAP Kinase Kinase 2MAP Kinase Signaling SystemMesodermMitogen-Activated Protein Kinase KinasesPhenotypePhosphatidylinositol 3-KinasesPromoter Regions, GeneticProtein Serine-Threonine KinasesProtein-Tyrosine KinasesSnail Family Transcription FactorsTranscription FactorsTransforming Growth Factor betaTransforming Growth Factor beta1Attribution-NonCommercial-NoDerivatives 4.0 Internacional12665527278232111310.1074/jbc.M211304200The Journal of biological chemistryopen access