Abstract
We found that ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] caused phosphorylation of mitogen-activated protein kinase (MAPK), followed by expression of neurofilament-M, a neuron-specific protein, in cultured PC12 rat pheochromocytoma cells. The ebselen-induced MAPK activation was suppressed by U0126, an inhibitor of MAPK kinase (MEK1/2), but not by K252a, a selective inhibitor of Trk family tyrosine kinases; AG1478, an antagonist of epidermal growth factor receptor (EGFR); pertussis toxin, an inhibitor of Gi/o; or GP antagonist-2A, an inhibitor of Gq. Furthermore, we observed that N-acetyl-L-cysteine, an inhibitor of tyrosine kinases, suppressed ebselen-induced MAPK activation and buthionine sulfoximine, an activator of protein tyrosine phosphatases, enhanced the effect, indicating that ebselen activated MEK1/2 through one or more tyrosine kinases. Based on these results, we propose that ebselen stimulated intracellular tyrosine kinase activity, thus activating a MAPK cascade (tyrosine kinase-MEK1/2-ERK1/2) in PC12 cells and that this activation resulted in their neuronal differentiation.
(c) 2007 Wiley-Liss, Inc.
MeSH terms
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Animals
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Antioxidants / chemistry
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Antioxidants / pharmacology*
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Azoles / chemistry
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Azoles / pharmacology*
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Butadienes / pharmacology
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Carbazoles / pharmacology
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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ErbB Receptors / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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GTP-Binding Protein alpha Subunits, Gi-Go / antagonists & inhibitors
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GTP-Binding Protein alpha Subunits, Gq-G11 / antagonists & inhibitors
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Indole Alkaloids / pharmacology
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Isoindoles
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Mitogen-Activated Protein Kinases / metabolism*
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Neurites / drug effects
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Neurites / metabolism
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Neurites / physiology
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Neurofilament Proteins / biosynthesis*
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Nitriles / pharmacology
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Organoselenium Compounds / chemistry
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Organoselenium Compounds / pharmacology*
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Oxidation-Reduction / drug effects
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PC12 Cells / drug effects
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PC12 Cells / metabolism*
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Pertussis Toxin / pharmacology
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Phosphorylation / drug effects
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Quinazolines
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Rats
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases / metabolism
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Selenium*
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Tyrphostins / pharmacology
Substances
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Antioxidants
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Azoles
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Butadienes
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Carbazoles
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Indole Alkaloids
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Isoindoles
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Neurofilament Proteins
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Nitriles
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Organoselenium Compounds
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Quinazolines
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Tyrphostins
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U 0126
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neurofilament protein M
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RTKI cpd
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ebselen
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staurosporine aglycone
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Pertussis Toxin
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ErbB Receptors
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Receptor Protein-Tyrosine Kinases
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinases
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GTP-Binding Protein alpha Subunits, Gi-Go
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GTP-Binding Protein alpha Subunits, Gq-G11
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Selenium