p38 maintains E-cadherin expression by modulating TAK1-NF-kappa B during epithelial-to-mesenchymal transition

Raffaele Strippoli, Ignacio Benedicto, Miguel Foronda, Maria Luisa Perez-Lozano, Sara Sánchez-Perales, Manuel López-Cabrera, Miguel Ángel Del Pozo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4321-31
Number of pages11
JournalJournal of Cell Science
Volume123
Issue numberPt 24
DOIs
Publication statusPublished - 15 Dec 2010

Keywords

  • Cadherins
  • Cell Nucleus
  • Cells, Cultured
  • Cytokines
  • DNA
  • Epithelial Cells
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation
  • Humans
  • Keratins
  • MAP Kinase Kinase Kinases
  • Models, Biological
  • NF-kappa B
  • Nuclear Proteins
  • Phenotype
  • Phosphorylation
  • Phosphoserine
  • Phosphothreonine
  • Protein Binding
  • Protein Phosphatase 2
  • Protein Transport
  • Transcription Factors
  • Transcription, Genetic
  • Twist Transcription Factor
  • p38 Mitogen-Activated Protein Kinases

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