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Synergetic activation of p38 mitogen-activated protein kinase and caspase-3-like proteases for execution of calyculin A-induced apoptosis but not N-methyl-d-aspartate-induced necrosis in mouse cortical neurons.

Ko, HW; Han, KS; Kim, EY; Ryu, BR; Yoon, WJ; Jung, YK; Kim, SU; Gwag, BJ
Journal of neurochemistry, 74(6):2455-2461, 2000
Journal Title
Journal of neurochemistry
We examined the possibility that p38 mitogen-activated protein kinase and caspase-3 would be activated for execution of apoptosis and excitotoxicity, the two major types of neuronal death underlying hypoxicischemic and neurodegenerative diseases. Mouse cortical cell cultures underwent widespread neuronal apoptosis 24 h following exposure to 10-30 nM calyculin A, a selective inhibitor of Ser/Thr phosphatase I and IIA. Activity of p38 was increased 2-4 h following exposure to 30 nM calyculin A. Addition of 3-10 microM PD169316, a selective p38 inhibitor, partially attenuated calyculin A neurotoxicity. Activity of caspase-3-like proteases was increased in cortical cell cultures exposed to 30 nM calyculin A for 8-16 h as shown by cleavage of DEVD-p-nitroanilide and phosphorylated tau. Proteolysis of tau was completely blocked by addition of 100 microM N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk), a broad-spectrum inhibitor of caspases, but incompletely by 10 microM PD169316. Calyculin A neurotoxicity was partially sensitive to 100 microM z-VAD-fmk. Cotreatment with 10 microM PD169316 and 100 microM z-VAD-fmk showed additive neuroprotection against calyculin A. Neither PD169316 nor z-VAD-fmk showed a beneficial effect against excitotoxic neuronal necrosis induced by exposure to 20 microM NMDA. Thus, caspase-3-like proteases and p38 likely contribute to calyculin A-induced neuronal apoptosis but not NMDA-induced neuronal necrosis.
MeSH terms
Amino Acid Chloromethyl Ketones/pharmacologyAnimalsApoptosis/drug effects/*physiologyCaspase 3Caspases/*metabolismCells, CulturedCerebral Cortex/cytologyCysteine Proteinase Inhibitors/pharmacologyDrug SynergismEnzyme Inhibitors/pharmacologyExcitatory Amino Acid Agonists/*pharmacologyFetus/cytologyImidazoles/pharmacologyMiceMitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolismN-Methylaspartate/*pharmacologyNecrosisNeurons/chemistry/*enzymology/pathologyNeurotoxins/pharmacologyOxazoles/*pharmacologyReceptors, N-Methyl-D-Aspartate/physiologyp38 Mitogen-Activated Protein Kinasestau Proteins/metabolism
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
Journal Papers > School of Medicine / Graduate School of Medicine > Neurology
AJOU Authors
김, 승업곽, 병주
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