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

O Cuvillier, G Pirianov, B Kleuser, PG Vanek, OA Coso… - Nature, 1996 - nature.com
Nature, 1996nature.com
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 …
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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