ERK1/2 regulates two sequential steps promoting monocyte survival to peroxynitrite.
Previous studies from our laboratory indicate that cytosolic phospholipase A(2) (cPLA(2))-released arachidonic acid promotes monocyte/macrophage survival in the presence of peroxynitrite. In particular, the lipid messenger is metabolised by 5-lipoxygenase (5-LO) to 5-hydroxyeicosatetraenoic acid and causes the mitochondrial translocation of protein kinase Calpha (PKCalpha), an event associated with the cytosolic accumulation of Bad and Bax. Here we show that phosphorylation reactions driven by extracellular regulated kinase 1/2 (ERK1/2) critically regulate the activation/nuclear translocation of 5-LO. Inhibition of ERK1/2 was invariably associated with the cytosolic localisation of PKCalpha, the mitochondrial accumulation of Bad and Bax and with a rapid mitochondrial permeability transition-dependent necrosis. All these events were prevented by nanomolar concentrations of 5-hydroxyeicosatetraenoic acid. Hence, in addition to the previously characterised effects on cPLA(2), ERK1/2 critically regulates 5-LO activity in the absence of additional downstream targets in the survival signalling preventing peroxynitrite toxicity.
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Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino "Carlo Bo", Via Santa Chiara, Urbino (PU), Italy.
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D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D020298:U937 Cells; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism
C494819:BAD protein, human; C494826:BAX protein, human; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D030421:Peroxynitrous Acid; D016718:Arachidonic Acid; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D016572:Cyclosporine; D045304:Cytochromes c; D001094:Arachidonate 5-Lipoxygenase; D051571:Protein Kinase C-alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010741:Phospholipases A