Ebselen, a redox regulator containing a selenium atom, induces neurofilament M expression in cultured rat pheochromocytoma PC12 cells via activation of mitogen-activated protein kinase.
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.
Nishina
Atsuyoshi
A
Gunma Industrial Technology Center, 884-1 Kamesato, Maebashi, Gunma, Japan. nishina@tec-lab.pref.gunma.jp
Sekiguchi
Akihiro
A
He
Yuxi
Y
Koketsu
Mamoru
M
Furukawa
Shoei
S
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001393:Azoles / Q000737:chemistry / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors; D026121:Indole Alkaloids / Q000494:pharmacology; D054833:Isoindoles; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D016900:Neurofilament Proteins / Q000096:biosynthesis*; D009570:Nitriles / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012643:Selenium; D020032:Tyrphostins / Q000494:pharmacology
D000975:Antioxidants; D001393:Azoles; D002070:Butadienes; D002227:Carbazoles; D026121:Indole Alkaloids; D054833:Isoindoles; D016900:Neurofilament Proteins; D009570:Nitriles; D016566:Organoselenium Compounds; D011799:Quinazolines; D020032:Tyrphostins; C113580:U 0126; C061195:neurofilament protein M; C101044:RTKI cpd; C042986:ebselen; C049985:staurosporine aglycone; D037342:Pertussis Toxin; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D012643:Selenium