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J. Biol. Chem., Vol. 279, Issue 34, 35903-35913, August 20, 2004
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Distinct Requirements for p38
and c-Jun N-terminal Kinase Stress-activated Protein Kinases in Different Forms of Apoptotic Neuronal Death*
**
From the
Department of Neurobiology, A. I. Virtanen Institute, University of Kuopio, P.O. Box 1627, Kuopio FIN 70211, Finland, the Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, and the ¶Turku Centre for Biotechnology, Åbo Akademi and University of Turku, Turku FIN 20521, Finland
The stress-activated protein kinases c-Jun-activated kinase (JNK) and p38 are implicated in neuronal apoptosis. Early studies in cell lines suggested a requirement for both in the apoptosis induced by withdrawal of nerve growth factor. However, studies in neuronal cells typically implicate JNK but not p38 in apoptosis. In some cases, p38 is implicated, but the role of JNK is undefined. It remains unclear whether p38 and JNK have differing roles dependent on cell type, apoptotic stimulus, or mechanism of cell death or whether they are redundant and each sufficient to induce identical forms of cell death. We investigate the relative roles of these protein kinases in different death mechanisms in a single system, cultured cerebellar granule neurons. Apoptosis induced by withdrawal of trophic support and glutamate are mechanistically different in terms of caspase activation, DNA fragmentation profile, chromatin morphology, and dependence on de novo gene expression. Caspase-independent apoptosis induced by glutamate is accompanied by strong activation of p38, and dominant negatives and inhibitors of the p38 pathway prevent this apoptosis. In contrast, withdrawal of trophic support induces caspase-dependent death accompanied by JNK-dependent phosphorylation of c-Jun, and inhibition of JNK is sufficient to prevent the death induced by withdrawal of trophic support. Inhibition of p38 does not block withdrawal of trophic support-induced death, nor does inhibition of JNK block glutamate-induced death. We propose that mechanistically different forms of apoptosis have differing requirements for p38 and JNK activities in neurons and demonstrate that only inhibition of the appropriate kinase will prevent neurons from undergoing apoptosis.
Received for publication, March 2, 2004 , and in revised form, May 24, 2004.
* This work was supported by Academy of Finland Grants 72446, 78232, 203520, and 206903, the A. I. Virtanen Institute graduate school, 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.
|| Supported by Åbo Akademi University.
** An Academy of Finland researcher. To whom correspondence should be addressed: A. I. Virtanen Institute, Neulaniementie 2, University of Kuopio, P.O. Box 1627, Kuopio, FIN-70211, Finland. Tel.: 358-17-163663; Fax: 358-17-163030; E-mail: courtney{at}messi.uku.fi.
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