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Ceramide activates the stress-activated protein kinases

J Biol Chem. 1995 Sep 29;270(39):22689-92. doi: 10.1074/jbc.270.39.22689.

Abstract

Tumor necrosis factor alpha (TNF alpha) activates the stress-activated protein kinases (SAPKs, also known as Jun nuclear kinases or JNKs) resulting in the stimulation of AP-1-dependent gene transcription and induces the translocation of NF kappa B to the nucleus resulting in the stimulation of NF kappa B-dependent gene transcription. A potential second messenger for these signaling pathways is ceramide, which is generated when TNF alpha activates sphingomyelinases. We show that treatment of HL-60 human promyelocytic cells with exogenous sphingomyelinase leads to rapid stimulation of JNK/SAPK activity, an effect not mimicked by treatment with phospholipase A2, C, or D. Further, JNK/SAPK activity is stimulated 2.7- and 2.8-fold, respectively, in cells exposed to C2-ceramide (5 microM) or TNF alpha (10 ng/ml). The prolonged stimulation of this kinase activity by C2-ceramide is similar to that previously reported for TNF alpha. In contrast, the related mitogen-activated protein kinases ERK1 and ERK2 are weakly stimulated following TNF alpha treatment (1.5-fold) and are inhibited by C2-ceramide treatment. TNF alpha also potently stimulates NF-kappa B DNA binding activity and transcriptional activity, but these effects are not mimicked by addition of C2-ceramide or sphingomyelinase to intact cells. Furthermore, TNF alpha, sphingomyelinase, and C2-ceramide induce c-jun, a gene that is stimulated by the ATF-2 and c-Jun transcription factors. These data suggest that ceramide may act as a second messenger for a subset of TNF alpha's biochemical and biological effects.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Ceramides / physiology*
  • Enzyme Activation
  • Gene Expression / drug effects
  • Genes, jun
  • HL-60 Cells
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Mice
  • Mitogen-Activated Protein Kinases*
  • Proto-Oncogene Proteins c-jun / biosynthesis
  • RNA, Messenger / analysis
  • RNA, Messenger / biosynthesis
  • Recombinant Proteins / pharmacology
  • Second Messenger Systems / drug effects
  • Second Messenger Systems / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Sphingomyelin Phosphodiesterase / pharmacology*
  • Stress, Physiological
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Ceramides
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Sphingomyelin Phosphodiesterase