title: Combined action of extracellular signal-regulated kinase and p38 kinase rescues Molt4 T cells from nitric oxide-induced apoptotic and necrotic cell death.
abstract: The mechanisms that regulate nitric oxide (NO)-induced apoptosis, especially in T cell apoptosis, are largely uncharacterized. Here, we report that protection from NO-induced cell death by phorbol 12-myristate 13-acetate (PMA) is dependent on both p38 and extracellular signal-regulated kinase (ERK) activation. Exposure of Molt4 cells to NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) induced both apoptotic and necrotic modes of cell death along with a sustained increase in p38 kinase phosphorylation. However, the p38 inhibitor SB202190 only slightly protected Molt4 cells from NO toxicity. In contrast, PMA rapidly phosphorylated both p38 kinase and ERK, and the phosphorylation statuses were not altered in the presence of SNAP. Interestingly, although each mitogen-activated protein kinase (MAPK) inhibitor by itself had only a modest effect, the combination of inhibitors for both MAPKs almost completely abolished the protective effect of PMA. Furthermore, dominant negative or catalytically inactive variants that modulate p38 and ERK mimicked the effects of MAPK inhibitors. We located the action of p38 and ERK upstream of the p53/mitochondrial membrane potential loss and caspases cascade. Together, these findings suggest that the PMA-induced activations of ERK and p38 kinase are parallel events that are both required for inhibition of NO-induced death of Molt4 cells.
authors.affiliation: Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan, Chonbuk 570-749, South Korea.
authors.forename: Hyun-Mee
authors.initials: HM
authors.lastname: Oh
authors.forename: Suck-Chei
authors.initials: SC
authors.lastname: Choi
authors.forename: Han-Sol
authors.initials: HS
authors.lastname: Lee
authors.forename: Churl-Hong
authors.initials: CH
authors.lastname: Chun
authors.forename: Geom-Seog
authors.initials: GS
authors.lastname: Seo
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Choi
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Lee
authors.forename: Myeung-Su
authors.initials: MS
authors.lastname: Lee
authors.forename: Joo-Jin
authors.initials: JJ
authors.lastname: Yeom
authors.forename: Suck-Jun
authors.initials: SJ
authors.lastname: Choi
authors.forename: Weon-Cheol
authors.initials: WC
authors.lastname: Han
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Oh
authors.forename: Yeun-Tai
authors.initials: YT
authors.lastname: Chung
authors.forename: Jang-Soo
authors.initials: JS
authors.lastname: Chun
authors.forename: Kang-Min
authors.initials: KM
authors.lastname: Lee
authors.forename: Chang-Duk
authors.initials: CD
authors.lastname: Jun
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002273:Carcinogens; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002384:Catalysis; D045744:Cell Line, Tumor; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009336:Necrosis; D009569:Nitric Oxide / Q000378:metabolism*; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010703:Phorbol Esters / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010703:Phorbol Esters; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; C110881:S-nitro-N-acetylpenicillamine; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D045304:Cytochromes c; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases; D010396:Penicillamine; D013755:Tetradecanoylphorbol Acetate; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole