Distinct sites of action of Bcl-2 and Bcl-xL in the ceramide pathway of apoptosis.
We studied the inhibition of tumour necrosis factor alpha (TNFalpha)- and camptothecin-induced apoptosis by Bcl-2 and Bcl-xL as they relate to the ceramide pathway. Expression of either Bcl-2 or Bcl-xL provided significant protection from the apoptotic effects of TNFalpha or camptothecin. In contrast to Bcl-2, Bcl-xL overexpression did not protect cells from ceramide-induced apoptosis. On the other hand, Bcl-xL prevented the accumulation of endogenous ceramide in response to TNFalpha or camptothecin, whereas Bcl-2 showed little effect on ceramide formation. Moreover, Bcl-xL, but not Bcl-2, totally inhibited a caspase-8-like activity in cell lysates stimulated with TNFalpha. These results identify a different mechanism of action for Bcl-xL compared with Bcl-2 and they demonstrate that Bcl-xL targets a point upstream of ceramide generation, whereas Bcl-2 functions downstream of ceramide in the TNFalpha- and camptothecin-activated pathways of apoptosis.
El-Assaad
W
W
American University of Beirut Medical Center, Department of Pediatrics, P.O. Box 113/6044, B21, Beirut, Lebanon.
El-Sabban
M
M
Awaraji
C
C
Abboushi
N
N
Dbaibo
G S
GS
D017209:Apoptosis; D001665:Binding Sites; D015153:Blotting, Western; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002518:Ceramides / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D002518:Ceramides; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases