c-Jun N-terminal protein kinase signalling pathway mediates lovastatin-induced rat brain neuroblast apoptosis.
We have previously shown that lovastatin, an HMG-CoA reductase inhibitor, induces apoptosis in rat brain neuroblasts. c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) are implicated in regulation of neuronal apoptosis. In this work, we investigated the role of JNK and p38 MAPK in neuroblast apoptosis induced by lovastatin. We found that lovastatin induced the activation of JNK, but not p38 MAPK. It also induced c-Jun phosphorylation with a subsequent increase in activator protein-1 (AP-1) binding, AP-1-mediated gene expression and BimEL protein levels. The effects of lovastatin were prevented by mevalonate. Pre-treatment with iJNK-I (a selective JNK inhibitor) prevented the effect of lovastatin on both neuroblast apoptosis and the activation of the JNK cascade. Furthermore, we found that the activation of the JNK signalling pathway triggered by lovastatin is accompanied by caspase-3 activation which is also inhibited by iJNK-I pre-treatment. Finally, a specific inhibitor of p38 MAPK, SB203580, had no effect on lovastatin-induced neuroblast apoptosis. Taken together, our data suggest that the activation of the JNK/c-Jun/BimEL signalling pathway plays a crucial role in lovastatin-induced neuroblast apoptosis. Our findings may also contribute to elucidate the intracellular mechanisms involved in the central nervous system side effects associated with statin therapy.
Cerezo-Guisado
Maria Isabel
MI
Departamento de Bioquímica, Biología Molecular y Genética, Facultad de Veterinaria, Avda de la Universidad s/n, Apdo. Correos 643, 10071 Cáceres, Spain.
Alvarez-Barrientos
Alberto
A
Argent
Ricardo
R
García-Marín
Luis Jesús
LJ
Bragado
Maria Julia
MJ
Lorenzo
Maria Jesús
MJ
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D008148:Lovastatin / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D008148:Lovastatin; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4