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C-Jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis

By S. Willaime-Morawek, K. Brami-Cherrier, J. Mariani, J. Caboche and B. Brugg

Abstract

Understanding the regulation of the apoptotic program<br/>in neurons by intracellular pathways is currently a subject<br/>of great interest. Recent results suggest that c-Jun N-terminal<br/>kinases (JNK), mitogen-activated protein kinases<br/>and the transcription factor c-Jun are important regulators of<br/>this cell death program in post-mitotic neurons following<br/>survival-factor withdrawal. Our study demonstrates that ceramide levels increase upon survival-factor withdrawal in primary cultured cortical neurons. Furthermore, survival-factor<br/>withdrawal or addition of exogenous c2-ceramide induces<br/>JNK pathway activation in these cells. Western blot analyses<br/>of JNK and c-Jun using phospho-specific antibodies reveal<br/>that JNK and subsequent c-Jun phosphorylation occur hours<br/>before the initiation of apoptosis, reflected morphologically<br/>by neurite retraction and fragmentation, cell-body shrinkage<br/>and chromatin fragmentation. Immunocytochemistry using<br/>the same antibodies shows that phospho-JNK are localized<br/>in the neurites of control neurons and translocate to the<br/>nucleus where phospho-c-Jun concurrently appears upon<br/>ceramide-induced apoptosis. To determine if ceramide-induced<br/>c-Jun activation is responsible for the induction of the<br/>apoptotic program, we performed transient transfections of a<br/>dominant negative form of c-Jun, truncated in its transactivation<br/>region. Our results show that DNc-Jun partially protects<br/>cortical neurons from ceramide-induced apoptosis.<br/>Treatment of dominant negative c-Jun-expressing neurons<br/>with the pharmacological inhibitor of p38 kinase, SB203580,<br/>completely blocked neuronal death. Thus our data show that<br/>p38 and JNK/c-Jun pathways cooperate to induce neuronal<br/>apoptosis

Topics: R1, RC0321
Year: 2003
OAI identifier: oai:eprints.soton.ac.uk:66392
Provided by: e-Prints Soton

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