title: The effect of sodium nitroprusside on survival and stress signaling in PC12 rat phaeochromocytoma cells expressing a dominant negative RasH mutant protein.
abstract: Toxic concentrations of the second messenger nitric oxide cause cellular stress leading to cell death. Ras proteins, possible targets of nitric oxide-induced nitrosylation, may act as mediators in nitrosative stress. To analyze the possible involvement of Ras proteins in nitric oxide cytotoxicity, a PC12 rat phaeochromocytoma cell line expressing a dominant negative Ras mutant protein was used in this study. Cytotoxic concentrations of the nitric oxide donor sodium nitroprusside activated several proapoptotic mechanisms, including stimulation of the stress kinase pathways mediated by c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), inhibition of the translation initiation factor eIF2α, induction and phosphorylation of the p53 protein, and inhibited Akt-mediated antiapoptotic signaling, independent of Ras function. Simultaneously, Ras-dependent stimulation of the prosurvival ERK pathway was also observed, followed by an increased activation of the caspase-9/caspase-3 cascade in cells with impaired Ras function. It is concluded that nitric oxide stimulation of multiple signaling pathways contributes to the cell death program, whereas concomitant activation of the Ras/ERK pathway provides a certain degree of protection.
authors.affiliation: Department of Medical Biology, Medical School, University of Pécs, Pécs, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Bátor
authors.forename: Judit
authors.initials: J
authors.lastname: Varga
authors.forename: József
authors.initials: J
authors.lastname: Szeberényi
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D053938:DNA Fragmentation; D004789:Enzyme Activation; D005799:Genes, Dominant; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D009599:Nitroprusside; D009569:Nitric Oxide; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D018631:ras Proteins