Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate.
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.
Cuvillier
O
O
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007, USA.
Pirianov
G
G
Kleuser
B
B
Vanek
P G
PG
Coso
O A
OA
Gutkind
S
S
Spiegel
S
S
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D002518:Ceramides / Q000037:antagonists & inhibitors* / Q000502:physiology; D004249:DNA Damage; D004789:Enzyme Activation; D018922:HL-60 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008246:Lysophospholipids; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008938:Mitosis / Q000502:physiology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000502:physiology; D000099157:Sphingosine Kinase
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002518:Ceramides; D048031:JNK Mitogen-Activated Protein Kinases; D008246:Lysophospholipids; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011493:Protein Kinase C; D013110:Sphingosine; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D000099157:Sphingosine Kinase; C064769:N-acetylsphingosine; C060506:sphingosine 1-phosphate