Modulation by caspases of tumor necrosis factor-stimulated c-Jun N-terminal kinase activation but not nuclear factor-kappa B signaling

A F Littlejohn, S J Tucker, A A A Mohamed, S McKay, M J Helms, P Vandenabeele, D J MacEwan

Research output: Contribution to journalArticle

Abstract

Tumour necrosis factor-alpha (TNF) is capable of activating many downstream signaling molecules via its two receptors TNFR1 and TNFR2. TNF can stimulate the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) as well as the stress induced kinase c-Jun N-terminal kinase (JNK) through mechanisms that are not fully delineated. NF-kappaB becomes activated mainly through TNFR1 while JNK can be stimulated by either TNF receptor subtype. TNF can also induce apoptosis within cells due to its ability to recruit procaspase-8 to TNFR1, which in turn induces the caspase proteolytic cascade. We provide evidence here in human cells, that TNF-induced JNK activation is under the influence of caspases while NF-kappaB activity is not. By using pharmacological inhibitors of caspases, we have shown that JNK activity is reduced following caspase inhibition, especially when caspase-3 is targeted. NF-kappaB activity, as assessed by IkappaBalpha or IkappaBbeta degradation, electrophoretic mobility shift assay and NF-kappaB gene reporter assays, is shown to be unaffected by caspase inhibition. Therefore, downstream TNF receptor signaling events are differentially influenced by caspases. (C) 2002 Elsevier Science Inc. All rights reserved.

Original languageEnglish
Pages (from-to)91-99
Number of pages9
JournalBiochemical Pharmacology
Volume65
Publication statusPublished - 2003

Keywords

  • human
  • signal transduction
  • apoptosis
  • inflammation
  • cytokine receptors
  • transcription factor
  • SITE-SPECIFIC PHOSPHORYLATION
  • APOPTOTIC CELL-DEATH
  • TNF-RECEPTOR
  • ALPHA
  • PROTEIN
  • PATHWAY
  • DOMAIN
  • JNK
  • LIGAND
  • RIP

Cite this

Littlejohn, A. F., Tucker, S. J., Mohamed, A. A. A., McKay, S., Helms, M. J., Vandenabeele, P., & MacEwan, D. J. (2003). Modulation by caspases of tumor necrosis factor-stimulated c-Jun N-terminal kinase activation but not nuclear factor-kappa B signaling. Biochemical Pharmacology, 65, 91-99.