Distinct Requirements for p38α and c-Jun N-terminal Kinase Stress-activated Protein Kinases in Different Forms of Apoptotic Neuronal Death

• Published in: The Journal of biological chemistry Vol. 279; no. 34; p. 35903
• Main Authors: Jiong Cao, Maria M. Semenova, Victor T. Solovyan, Jiahuai Han, Eleanor T. Coffey, Michael J. Courtney
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 20-08-2004
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M402353200

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.