Role for ceramide as an endogenous mediator of Fas-induced cytotoxicity.
Triggering of the Fas/APO-1 cell-surface receptor induces apoptosis through an uncharacterized chain of events. Exposure of Fas-sensitive cells to an agonist monoclonal antibody induced cell death and a 200-300% elevation in endogenous levels of the sphingolipid ceramide, a proposed intracellular mediator of apoptosis. In contrast, similar treatment of Fas-resistant cells caused insignificant changes in ceramide levels. Because resistant cell lines expressed the Fas antigen, these results indicate that these cells have a defect in the proximal signaling events leading to ceramide generation. Exposure of the resistant cell lines to a synthetic analog of ceramide induced apoptosis, thus bypassing Fas resistance and indicating that the signaling pathways downstream of ceramide were intact. Furthermore, activation of protein kinase C with the diacylglycerol analog phorbol 12-myristate 13-acetate significantly reduced Fas-induced cytotoxicity, suggesting opposing roles for ceramide and protein kinase C in regulation of apoptosis. These results provide evidence for ceramide as a necessary and sufficient lipid mediator of Fas-mediated apoptosis and suggest this process may be modulated via activation of additional signal-transduction pathways.
Tepper
C G
CG
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Jayadev
S
S
Liu
B
B
Bielawska
A
A
Wolff
R
R
Yonehara
S
S
Hannun
Y A
YA
Seldin
M F
MF
D000954:Antigens, Surface / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D002518:Ceramides / Q000096:biosynthesis / Q000502:physiology*; D004789:Enzyme Activation; D006868:Hydrolysis; D010641:Phenotype; D011493:Protein Kinase C / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D019014:fas Receptor
D000954:Antigens, Surface; D002518:Ceramides; D013109:Sphingomyelins; D019014:fas Receptor; D011493:Protein Kinase C