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J. Biol. Chem., Vol. 278, Issue 25, 22357-22366, June 20, 2003

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JNK-independent Activation of c-Jun during Neuronal Apoptosis Induced by Multiple DNA-damaging Agents^*

Cagri Giray Besirli  and Eugene Malcolm Johnson, Jr. 

From the Departments of Neurology and Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

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.

Received for publication, January 22, 2003 , and in revised form, March 13, 2003.

^* This work was supported by National Institutes of Health Grants R37AG-12947 and RO1NS38651. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Member of the Medical Scientist Training Program at Washington University School of Medicine.

To whom correspondence should be addressed: 660 South Euclid, Campus Box 8103, St. Louis, MO 63110. Tel.: 314-362-3926; Fax: 314-747-1772; E-mail: ejohnson{at}pcg.wustl.edu.

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