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J. Biol. Chem., Vol. 283, Issue 28, 19704-19713, July 11, 2008

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All JNKs Can Kill, but Nuclear Localization Is Critical for Neuronal Death^*

Benny Björkblom, Jenni C. Vainio, Vesa Hongisto, Thomas Herdegen, Michael J. Courtney^¶1, and Eleanor T. Coffey¹²

From the Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, FIN 20521 Finland, the Institute of Pharmacology, 24105 Kiel, Germany, and the ^¶Department of Neurobiology, A.I. Virtanen Institute, University of Kuopio, Kuopio FIN 70211, Finland

JNKs are implicated in a range of brain pathologies and receive considerable attention as potential therapeutic targets. However, JNKs also regulate physiological and homeostatic processes. An attractive hypothesis from the drug development perspective is that distinct JNK isoforms mediate "physiological" and "pathological" responses. However, this lacks experimental evaluation. Here we investigate the isoforms, subcellular pools, and c-Jun/ATF2 targets of JNK in death of central nervous system neurons following withdrawal of trophic support. We use gene knockouts, gene silencing, subcellularly targeted dominant negative constructs, and pharmacological inhibitors. Combined small interfering RNA knockdown of all JNKs 1, 2, and 3, provides substantial neuroprotection. In contrast, knockdown or knock-out of individual JNKs or two JNKs together does not protect. This explains why the evidence for JNK in neuronal death has to date been largely pharmacological. Complete knockdown of c-Jun and ATF2 using small interfering RNA also fails to protect, casting doubt on c-Jun as a critical effector of JNK in neuronal death. Nonetheless, the death requires nuclear but not cytosolic JNK activity as nuclear dominant negative inhibitors of JNK protect, whereas cytosolic inhibitors only block physiological JNK function. Thus any one of the three JNKs is capable of mediating apoptosis and inhibition of nuclear JNK is protective.

Received for publication, September 14, 2007 , and in revised form, May 2, 2008.

^* This work was supported by grants from the Academy of Finland (Grants 206497, 72608, 78232, and 203520), the Magnus Ehrnrooth Foundation, the Informational and Structural Biology Graduate School, the Finnish Graduate School in Neuroscience, the Turku Graduate School of Biomedical Sciences, the European Union Sixth framework STRESSPROTECT, Åbo Akademi University, and the University of Kuopio. 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Turku Centre for Biotechnology, Åbo Akademi and Turku University, Biocity, Tykistokatu 6, Turku 20521, Finland. Tel.: 358-2-3338605; Fax: 358-2-3338000; E-mail: ecoffey{at}btk.fi.

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