Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate

Nature. 1996 Jun 27;381(6585):800-3. doi: 10.1038/381800a0.


Ceramide is an important regulatory participant of programmed cell death (apoptosis) induced by tumour-necrosis factor (TNF)-alpha and Fas ligand, members of the TNF superfamily. Conversely, sphingosine and sphingosine-1-phosphate, which are metabolites of ceramide, induce mitogenesis and have been implicated as second messengers in cellular proliferation induced by platelet-derived growth factor and serum. Here we report that sphingosine-1-phosphate prevents the appearance of the key features of apoptosis, namely intranucleosomal DNA fragmentation and morphological changes, which result from increased concentrations of ceramide. Furthermore, inhibition of ceramide-mediated apoptosis by activation of protein kinase C results from stimulation of sphingosine kinase and the concomitant increase in intracellular sphingosine-1-phosphate. Finally sphingosine-1-phosphate not only stimulates the extracellular signal-regulated kinase (ERK) pathway, it counteracts the ceramide-induced activation of stress-activated protein kinase (SAPK/JNK). Thus, the balance between the intracellular levels of ceramide and sphingosine-1-phosphate and their regulatory effects on different family members of mitogen-activated protein kinases determines the fate of the cell.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Apoptosis / physiology*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cells, Cultured
  • Ceramides / antagonists & inhibitors*
  • Ceramides / physiology
  • DNA Damage
  • Enzyme Activation
  • HL-60 Cells
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Lysophospholipids*
  • Mice
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Mitosis / physiology
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Signal Transduction
  • Sphingosine / analogs & derivatives*
  • Sphingosine / physiology
  • Tumor Necrosis Factor-alpha / physiology
  • fas Receptor / physiology


  • Ceramides
  • Lysophospholipids
  • N-acetylsphingosine
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Sphingosine