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Originally published In Press as doi:10.1074/jbc.M204362200 on June 28, 2002

J. Biol. Chem., Vol. 277, Issue 38, 35586-35596, September 20, 2002
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Interaction of the c-Jun/JNK Pathway and Cyclin-dependent Kinases in Death of Embryonic Cortical Neurons Evoked by DNA Damage*

Mohammad H. GhahremaniDagger §, Elizabeth KeramarisDagger , Tanaya ShreeDagger , Zhengui Xia, Roger J. Davis||, Richard Flavell**, Ruth S. SlackDagger , and David S. ParkDagger Dagger Dagger

From the Dagger  Neuroscience Research Institute, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, the  Department of Environmental Health and Pharmacology, Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, Washington 98195, the || Department of Biochemistry and Molecular Biology, Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, and the ** Section of Immunobiology, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, Connecticut 06520

DNA damage, an important initiator of neuronal death, has been implicated in numerous neurodegenerative conditions. We previously delineated several pathways that control embryonic cortical neuronal death evoked by the DNA-damaging agent, camptothecin. In this model, the tumor suppressor p53 and cyclin-dependent kinases (CDKs) are activated independently and cooperate to mediate the conserved death pathway. To further our understanding, we presently examined whether the c-Jun/JNK pathway modulates death and whether this pathway is regulated by CDKs, p53, and Bax. We show that c-Jun/JNK is activated following DNA damage. Moreover, the c-Jun pathway is one mediator of death, because expression of dominant negative c-Jun and cdc42, and JNK pathway inhibitors are neuroprotective. Although previous evidences indicate that JNK3 is required for neuronal death under certain conditions, we show that JNK3 deficiency only partially mediates c-Jun phosphorylation and its deficiency does not protect neurons from death. Interestingly, we provide evidence that CDK activity regulates c-Jun but does not affect upstream pathways that lead to JNK phosphorylation. Finally, c-Jun activation is independent of p53 and Bax. Accordingly, we propose that c-Jun is regulated by the JNK and CDK pathways and that both must be activated for efficient c-Jun activation to occur.

* This work was supported in part by the Ontario Neurotrauma Foundation, Heart and Stroke Foundation of Ontario, Canadian Stroke Network, and Canadian Institute of Health Research (to D. S. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Recipient of a Canadian Stroke Network fellowship.

Dagger Dagger To whom correspondence should be addressed. Tel.: 613-562-5800 (ext. 8816); Fax: 613-562-5403; E-mail: dpark@uottawa.ca.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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