Role of oxidative stress and JNK pathway in apoptotic death induced by potassium deprivation and staurosporine in cerebellar granule neurons.
Several signaling pathways are differentially activated during apoptotic cell death. We have previously found that during apoptotic death of cerebellar granule neurons (CGN) induced by potassium deprivation (K5) and staurosporine there is an increase in the generation of reactive oxygen species (ROS). The inhibition of ROS generation reduces the extent of cell death. However, remain to be elucidated the mechanisms by which ROS participate in this apoptotic process. On the other hand, it is well known that c-Jun amino-terminal kinase (JNK) pathway plays a pivotal role in cell death of several cell types. In the present study we found that K5 activated the JNK pathway and that its inhibition with SP600125 markedly prevented caspase 3 activation, nuclear condensation and cell death induced by K5. In contrast, JNK pathway was not activated by staurosporine and the JNK inhibitor did not affect cell death induced by this stimulus. We also found that JNK inhibition did not affect ROS levels induced by K5 or staurosporine, suggesting that ROS are upstream of JNK pathway activation. Antioxidants increased ASK1 phosphorylation and decreased JNK1/2 and c-Jun phosphorylation induced by K5. According to these results, we suggest that apoptosis induced by K5 is JNK-dependent and mediated by ROS, but apoptosis induced by staurosporine is not dependent on JNK and that the observed ROS generation by staurosporine seems not to be involved in the activation of this signaling pathway.
Ramiro-Cortés
Yazmín
Y
Institute of Cell Physiology, National University of Mexico, Mexico City, Mexico.
Morán
Julio
J
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D007008:Hypokalemia / Q000503:physiopathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D044949:Kaempferols / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology*
D000975:Antioxidants; D004791:Enzyme Inhibitors; D044949:Kaempferols; D017382:Reactive Oxygen Species; C006552:kaempferol; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D019311:Staurosporine