JNK-independent activation of c-Jun during neuronal apoptosis induced by multiple DNA-damaging agents.
Activation of the JNK pathway and induction of the AP-1 transcription factor c-Jun are critical for neuronal apoptosis caused by a variety of insults. Ara-C-induced DNA damage caused rapid sympathetic neuronal death that was associated with an increase of c-jun expression. In addition, c-Jun was phosphorylated in its N-terminal transactivation domain, which is important for c-Jun-mediated gene transcription. Blocking c-Jun activation by JNK pathway inhibition prevented neuronal death after stress. In contrast, neither the JNK inhibitor SP600125 nor the mixed lineage kinase inhibitor CEP-1347 prevented cytosine arabinoside-induced neuronal death, demonstrating that the JNK pathway was not necessary for DNA damage-induced neuronal apoptosis. Surprisingly, SP600125 or CEP-1347 could not block c-Jun induction or phosphorylation after DNA damage. Pharmacological inhibitors of cyclin-dependent kinase (CDK) activity completely prevented c-Jun phosphorylation after DNA damage. These results demonstrate that c-Jun activation during DNA damage-induced neuronal apoptosis was independent of the classical JNK pathway and was mediated by a novel c-Jun kinase. Based on pharmacological criteria, DNA damage-induced neuronal c-Jun kinase may be a member of the CDK family or be activated by a CDK-like kinase. Activation of this novel kinase and subsequent phosphorylation of c-Jun may be important in neuronal death after DNA damage.
Besirli
Cagri Giray
CG
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Johnson
Eugene Malcolm
EM
D000818:Animals; D000831:Animals, Newborn; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002227:Carbazoles / Q000494:pharmacology*; D018929:Cell Culture Techniques / Q000379:methods; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000873:Anthracenes; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D003561:Cytarabine; C106592:3,9-bis((ethylthio)methyl)-K-252a; C432165:pyrazolanthrone; D005047:Etoposide; D004247:DNA; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases