Programmed cell death induced by ceramide.
Sphingomyelin hydrolysis and ceramide generation have been implicated in a signal transduction pathway that mediates the effects of tumor necrosis factor-alpha (TNF-alpha) and other agents on cell growth and differentiation. In many leukemic cells, TNF-alpha causes DNA fragmentation, which leads to programmed cell death (apoptosis). C2-ceramide (0.6 to 5 microM), a synthetic cell-permeable ceramide analog, induced internucleosomal DNA fragmentation, which was inhibited by zinc ion. Other amphiphilic lipids failed to induce apoptosis. The closely related C2-dihydroceramide was also ineffective, which suggests a critical role for the sphingolipid double bond. The effects of C2-ceramide on DNA fragmentation were prevented by the protein kinase C activator phorbol 12-myristate 13-acetate, which suggests the existence of two opposing intracellular pathways in the regulation of apoptosis.
Obeid
L M
LM
Department of Medicine, Duke University Medical Center, Durham, NC 27710.
Linardic
C M
CM
Karolak
L A
LA
Hannun
Y A
YA
D017209:Apoptosis / Q000187:drug effects*; D002518:Ceramides / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D007938:Leukemia; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology
D002518:Ceramides; D009707:Nucleosomes; D013109:Sphingomyelins; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D011493:Protein Kinase C; D015032:Zinc; D013755:Tetradecanoylphorbol Acetate