Requirement of AP-1 for ceramide-induced apoptosis in human leukemia HL-60 cells.
Ceramide has emerged as a novel lipid mediator in cell proliferation, differentiation, and apoptosis. In this work, we demonstrate that the levels of c-jun mRNA, c-Jun protein, and DNA binding activity of a nuclear transcription factor AP-1 to 12-o-tetradecanoylphorbol 13-acetate responsive elements all increased following treatment with the cell-permeable ceramide, N-acetylsphingosine in human leukemia HL-60 cells. N-Acetylsphingosine (1-10 microM) increased the levels of c-jun mRNA in a dose-dependent manner, and maximal expression was achieved 1 h after treatment. Increase of c-jun expression treated with 5 microM N-acetyldihydrosphingosine, which could not induce apoptosis, was one third of that with 5 microM N-acetylsphingosine. Ceramide-induced growth inhibition and DNA fragmentation were both prevented by treatment with curcumin, 1,7-bis[4-hydroxy-3-methoxy-phenyl]-1,6-heptadiene-3,5-dione (an inhibitor of AP-1 activation), or antisense oligonucleotides for c-jun. These results suggest that the transcription factor AP-1 is critical for apoptosis in HL-60 cells and that an intracellular sphingolipid mediator, ceramide, modulates a signal transduction inducing apoptosis through AP-1 activation.
Sawai
H
H
Department of Internal Medicine, Faculty of Medicine, Kyoto University, Japan.
Okazaki
T
T
Yamamoto
H
H
Okano
H
H
Takeda
Y
Y
Tashima
M
M
Sawada
H
H
Okuma
M
M
Ishikura
H
H
Umehara
H
H
D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D003474:Curcumin / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D016758:Genes, jun; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; C064769:N-acetylsphingosine; D016376:Oligonucleotides, Antisense; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D003474:Curcumin; D013110:Sphingosine