title: p38 maintains E-cadherin expression by modulating TAK1-NF-kappa B during epithelial-to-mesenchymal transition.
abstract: Epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells is a pathological process that occurs during peritoneal dialysis. EMT leads to peritoneal fibrosis, ultrafiltration failure and eventually to the discontinuation of therapy. Signaling pathways involved in mesothelial EMT are thus of great interest, but are mostly unknown. We used primary mesothelial cells from human omentum to analyze the role of the p38 MAPK signaling pathway in the induction of EMT. The use of specific inhibitors, a dominant-negative p38 mutant and lentiviral silencing of p38α demonstrated that p38 promotes E-cadherin expression both in untreated cells and in cells co-stimulated with the EMT-inducing stimuli transforming growth factor (TGF)-β1 and interleukin (IL)-1β. p38 inhibition also led to disorganization and downregulation of cytokeratin filaments and zonula occludens (ZO)-1, whereas expression of vimentin was increased. Analysis of transcription factors that repress E-cadherin expression showed that p38 blockade inhibited expression of Snail1 while increasing expression of Twist. Nuclear translocation and transcriptional activity of p65 NF-κB, an important inducer of EMT, was increased by p38 inhibition. Moreover, p38 inhibition increased the phosphorylation of TGF-β-activated kinase 1 (TAK1), NF-κB and IκBα. The effect of p38 inhibition on E-cadherin expression was rescued by modulating the TAK1-NF-κB pathway. Our results demonstrate that p38 maintains E-cadherin expression by suppressing TAK1-NF-κB signaling, thus impeding the induction of EMT in human primary mesothelial cells. This represents a novel role of p38 as a brake or 'gatekeeper' of EMT induction by maintaining E-cadherin levels.
authors.affiliation: Integrin Signaling Laboratory, Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Strippoli
authors.forename: Ignacio
authors.initials: I
authors.lastname: Benedicto
authors.forename: Miguel
authors.initials: M
authors.lastname: Foronda
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Perez-Lozano
authors.forename: Sara
authors.initials: S
authors.lastname: Sánchez-Perales
authors.forename: Manuel
authors.initials: M
authors.lastname: López-Cabrera
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Del Pozo
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007633:Keratins / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D010769:Phosphothreonine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D016207:Cytokines; D004247:DNA; D007633:Keratins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D009687:Nuclear Proteins; D010768:Phosphoserine; D010769:Phosphothreonine; D054648:Protein Phosphatase 2; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C513384:CDH1 protein, human; C000604407:SNAI1 protein, human; C103173:TWIST1 protein, human