The role of c-Jun kinase in the apoptotic response to nucleoside analogue-induced DNA damage.
Activation of the c-Jun NH2-terminal kinase type 1 (JNK1) signaling pathway is often associated with apoptosis. In this report, we elucidated the role of this kinase in the programmed cell death induced by the nucleoside analogue 9-beta-D-arabinosyl-2-fluoroadenine (F-ara-A). Treatment of ML-1 cells with 3 or 10 microM F-ara-A specifically killed cells in the S-phase of the population. Incorporation of F-ara-ATP, the nucleoside triphosphate of F-ara-A, into DNA resulted in the activation of JNK1 in a time- and dose-dependent fashion. Activation of JNK1 temporally preceded DNA fragmentation. When incorporation of F-ara-A into DNA was blocked by pretreatment of the cells with aphidicolin to inhibit DNA synthesis, neither JNK1 signaling nor apoptosis was evident. Furthermore, inhibition of JNK1 by treatment of the cells with forskolin or by pretreatment with an antisense oligonucleotide directed against JNK1 mRNA resulted in a decrease in F-ara-A-induced apoptosis. Finally, the JNK1 signaling pathway appeared to be upstream to that of the effector caspases in nucleoside analogue-induced apoptosis. Thus, our data strongly suggest that JNK1 is involved in transduction of F-ara-A-induced distress signals into an apoptotic response.
Sampath
D
D
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Plunkett
W
W
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001088:Arabinonucleotides / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007951:Leukemia, Myeloid; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D016196:S Phase / Q000502:physiology; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives* / Q000378:metabolism
D000970:Antineoplastic Agents; D001088:Arabinonucleotides; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; C034957:2-fluoro-araATP; D004247:DNA; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases; D014740:Vidarabine; C024352:fludarabine