title: Activation of the mitochondrial caspase cascade in the absence of protein synthesis does not require c-Jun N-terminal kinase.
abstract: Prolonged activation of the c-Jun N-terminal kinase (JNK) has been suggested as a signal for apoptosis in response to a wide variety of stimuli. Using three cytocidal RNA or protein synthesis inhibitors (actinomycin D, anisomycin, and emetine), the potential role of JNK in activation of the mitochondrial apoptotic cascade was investigated in A549-S cells. Protein synthesis inhibition per se was not the cause of cell death as cycloheximide induced only growth arrest. All the cytocidal inhibitors induced cytochrome c release and caspases 9 activation within hours, but only anisomycin caused persistent JNK activation. Although, the JNK inhibitor, SP600125, inhibited JNK-dependent anisomycin-induced c-Jun phosphorylation, it was ineffective in preventing anisomycin-induced caspase activation and cell death. Thus, all three lethal macromolecule synthesis inhibitors can activate the mitochondrial apoptotic machinery independent of JNK activation, demonstrating that the mitochondrial apoptotic pathway can be activated independently of the JNK pathway in the absence of protein synthesis.
authors.affiliation: Department of Environmental Health Sciences, School of Public Health and Center for Free Radical Biology, University of Alabama at Birmingham, RPHB-317, 1530 3rd Ave.S., Birmingham, AL 35294-0022, USA.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Watanabe
authors.forename: Takeo
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Dale A
authors.initials: DA
authors.lastname: Dickinson
authors.forename: Karen E
authors.initials: KE
authors.lastname: Iles
authors.forename: Henry Jay
authors.initials: HJ
authors.lastname: Forman
mesh_terms: D000841:Anisomycin / Q000494:pharmacology; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D003574:Cytochrome c Group / Q000187:drug effects / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004640:Emetine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000187:drug effects; D013997:Time Factors
chemical_list: D000873:Anthracenes; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D011506:Proteins; D003609:Dactinomycin; C432165:pyrazolanthrone; D000841:Anisomycin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; D004640:Emetine