Abstract
CERAMIDE is an important regulatory participant of programmed cell death (apoptosis) induced by tumour-necrosis factor (TNF)-α and Fas ligand, members of the TNF superfamily1–6. Conversely, sphingosine and sphingosine-1-phosphate, which are metabolites of ceramide, induce mitogenesis7 and have been implicated as second messengers in cellular proliferation induced by platelet-derived growth factor and serum8,9. 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) pathway10, 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 kineses determines the fate of the cell.
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Cuvillier, O., Pirianov, G., Kleuser, B. et al. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 381, 800–803 (1996). https://doi.org/10.1038/381800a0
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DOI: https://doi.org/10.1038/381800a0
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