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Scientific article
English

Osmoprotective transcription factor NFAT5/TonEBP modulates nuclear factor-kappaB activity

Published inMolecular biology of the cell, vol. 21, no. 19, p. 3459-3474
Publication date2010
Abstract

Tonicity-responsive binding-protein (TonEBP or NFAT5) is a widely expressed transcription factor whose activity is regulated by extracellular tonicity. TonEBP plays a key role in osmoprotection by binding to osmotic response element/TonE elements of genes that counteract the deleterious effects of cell shrinkage. Here, we show that in addition to this "classical" stimulation, TonEBP protects cells against hypertonicity by enhancing nuclear factor-kappaB (NF-kappaB) activity. We show that hypertonicity enhances NF-kappaB stimulation by lipopolysaccharide but not tumor necrosis factor-alpha, and we demonstrate overlapping protein kinase B (Akt)-dependent signal transduction pathways elicited by hypertonicity and transforming growth factor-alpha. Activation of p38 kinase by hypertonicity and downstream activation of Akt play key roles in TonEBP activity, IkappaBalpha degradation, and p65 nuclear translocation. TonEBP affects neither of these latter events and is itself insensitive to NF-kappaB signaling. Rather, we reveal a tonicity-dependent interaction between TonEBP and p65 and show that NF-kappaB activity is considerably enhanced after binding of NF-kappaB-TonEBP complexes to kappaB elements of NF-kappaB-responsive genes. We demonstrate the key roles of TonEBP and Akt in renal collecting duct epithelial cells and in macrophages. These findings reveal a novel role for TonEBP and Akt in NF-kappaB activation on the onset of hypertonic challenge.

Keywords
  • Cell Nucleus/drug effects/metabolism
  • Hep G2 Cells
  • Humans
  • Hypertonic Solutions/pharmacology
  • I-kappa B Proteins/metabolism
  • Macrophages/drug effects/enzymology
  • Models, Biological
  • NF-kappa B/*metabolism
  • *Osmosis/drug effects
  • Protein Binding/drug effects
  • Protein Processing, Post-Translational/drug effects
  • Protein Transport/drug effects
  • Proto-Oncogene Proteins c-akt/metabolism
  • Signal Transduction/drug effects
  • Transcription Factor RelA/metabolism
  • Transcription Factors/*metabolism
  • Transforming Growth Factor alpha/pharmacology
  • Tumor Necrosis Factor-alpha/pharmacology
  • P38 Mitogen-Activated Protein Kinases/metabolism
Citation (ISO format)
ROTH, Isabelle et al. Osmoprotective transcription factor NFAT5/TonEBP modulates nuclear factor-kappaB activity. In: Molecular biology of the cell, 2010, vol. 21, n° 19, p. 3459–3474. doi: 10.1091/mbc.E10-02-0133
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ISSN of the journal1059-1524
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