Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenal Gland Neoplasms
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Animals
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Enzyme Inhibitors / pharmacology*
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Flavonoids / pharmacology*
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Kinetics
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Mitochondria / drug effects
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Mitochondria / metabolism*
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism*
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PC12 Cells
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Pheochromocytoma
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Phosphorylation
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Proto-Oncogene Proteins c-raf / antagonists & inhibitors*
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Rats
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Reactive Oxygen Species / metabolism*
Substances
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Enzyme Inhibitors
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Flavonoids
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Reactive Oxygen Species
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one