Arsenite-induced apoptosis in cortical neurons is mediated by c-Jun N-terminal protein kinase 3 and p38 mitogen-activated protein kinase.
c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase are activated by stress and are implicated in regulation of apoptosis in several tissues. However, their contribution to stress-induced apoptosis in CNS neurons is not well defined. Here we investigated the role of JNK and p38 in cortical neuron apoptosis caused by sodium arsenite treatment. Sodium arsenite is an environmental toxicant that causes developmental defects in the CNS. Treatment of cortical neurons with sodium arsenite activated p38 and JNK3 but not JNK1 or JNK2. It also induced c-Jun phosphorylation. Furthermore, sodium arsenite induced cortical neuron apoptosis. This apoptosis was attenuated by SB203580, an inhibitor of p38, and by CEP-1347, an inhibitor of JNK activation. Expression of dominant-interfering mutants of the JNK or p38 pathways inhibited apoptosis induced by arsenite, whereas expression of constitutive active mutants for either pathway induced apoptosis. Moreover, the caspase inhibitor zVAD-fluoromethylketone as well as expression of bcl-2 or bcl-xL inhibited cortical neuron apoptosis induced by arsenite or by constitutive activation of JNK or p38. These data indicate that both JNK and p38 contribute to arsenite-induced apoptosis in primary CNS neurons, and this apoptosis requires the bcl-2-caspase pathway. This is the first evidence that a specific JNK isoform is differentially activated by stress and contributes to neuronal apoptosis.
Namgung
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Toxicology Program, Department of Environmental Health, and Graduate Programs in Neurobiology and Behavior and Molecular and Cell Biology, University of Washington, Seattle, Washington 98195, USA.
Xia
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D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D018053:Arsenites / Q000494:pharmacology*; D016923:Cell Death; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000502:physiology; D007700:Kinetics; D048057:Mitogen-Activated Protein Kinase 10; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017670:Sodium Compounds / Q000494:pharmacology*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases
D018053:Arsenites; D017670:Sodium Compounds; C017947:sodium arsenite; D048057:Mitogen-Activated Protein Kinase 10; D048056:Mitogen-Activated Protein Kinase 9; D011505:Protein-Tyrosine Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases