Sphingosine 1-phosphate inhibits activation of caspases that cleave poly(ADP-ribose) polymerase and lamins during Fas- and ceramide-mediated apoptosis in Jurkat T lymphocytes.
Ceramide, a sphingolipid generated by the hydrolysis of membrane-associated sphingomyelin, appears to play a role as a gauge of apoptosis. A further metabolite of ceramide, sphingosine 1-phosphate (SPP), prevents ceramide-mediated apoptosis, and it has been suggested that the balance between intracellular ceramide and SPP levels may determine the cell fate (Cuvillier, O., Pirianov, G, Kleuser, B., Vanek, P. G., Coso, O. A., Gutkind, J. S., and Spiegel, S. (1996) Nature 381, 800-803). Here, we investigated the role of SPP and the protein kinase C activator, phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), in the caspase cascade leading to the proteolysis of poly(ADP-ribose) polymerase (PARP) and lamins. In Jurkat T cells, Fas ligation or addition of exogenous C2-ceramide induced activations of caspase-3/CPP32 and caspase-7/Mch3 followed by PARP cleavage, effects that can be blocked either by SPP or TPA. Furthermore, both SPP and TPA inhibit the activation of caspase-6/Mch2 and subsequent lamin B cleavage. Ceramide, in contrast to Fas ligation, did not induce activation of caspase-8/FLICE and neither SPP nor TPA were able to prevent this activation. Thus, SPP, likely generated via protein kinase C-mediated activation of sphingosine kinase, suppresses the apoptotic pathway downstream of FLICE but upstream of the executioner caspases, caspase-3, -6, and -7.
Cuvillier
O
O
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, District of Columbia 20007, USA.
Rosenthal
D S
DS
Smulson
M E
ME
Spiegel
S
S
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053178:Caspase 6; D053179:Caspase 7; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D034921:Lamin Type B; D034882:Lamins; D008246:Lysophospholipids; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
D034921:Lamin Type B; D034882:Lamins; D008246:Lysophospholipids; C064769:N-acetylsphingosine; D009687:Nuclear Proteins; D019014:fas Receptor; D011064:Poly Adenosine Diphosphate Ribose; C060506:sphingosine 1-phosphate; C505407:CASP3 protein, human; C505514:CASP6 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053178:Caspase 6; D053179:Caspase 7; D020169:Caspases; D003546:Cysteine Endopeptidases; D013110:Sphingosine; D013755:Tetradecanoylphorbol Acetate