The Raf/MEK inhibitor PD98059 enhances ERK1/2 phosphorylation mediated by peroxynitrite via enforced mitochondrial formation of reactive oxygen species.
Exposure of PC12 cells to 100 microM peroxynitrite promotes phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) sensitive to PD98059 or U0126. At higher concentrations, however, ERK1/2 phosphorylation was prevented by U0126 and increased by PD98059 via a U0126-sensitive mechanism. PD98059, unlike U0126, enhanced the peroxynitrite-dependent formation of reactive oxygen species (ROS). These results, along with others obtained using respiratory chain inhibitors and respiration-deficient cells, lead to the conclusion that PD98059, while effectively inhibiting the peroxynitrite-induced Raf/MEK signaling leading to ERK1/2 phosphorylation, promotes an enforced mitochondrial formation of ROS inducing ERK1/2 phosphorylation via a Raf-1-independent/MEK-dependent mechanism.
Cerioni
Liana
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Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino Carlo Bo, Via S. Chiara 27, 61029 (PU), Urbino, Italy.
Palomba
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Orazio
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D000310:Adrenal Gland Neoplasms; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016716:PC12 Cells; D010673:Pheochromocytoma; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D017382:Reactive Oxygen Species; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one