Willaime-Morawek, S., Brami-Cherrier, K., Mariani, J., Caboche, J. and Brugg, B.
C-Jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis.
Neuroscience, 119, (2), . (doi:10.1016/S0306-4522(02)00996-X).
Understanding the regulation of the apoptotic program
in neurons by intracellular pathways is currently a subject
of great interest. Recent results suggest that c-Jun N-terminal
kinases (JNK), mitogen-activated protein kinases
and the transcription factor c-Jun are important regulators of
this cell death program in post-mitotic neurons following
survival-factor withdrawal. Our study demonstrates that ceramide levels increase upon survival-factor withdrawal in primary cultured cortical neurons. Furthermore, survival-factor
withdrawal or addition of exogenous c2-ceramide induces
JNK pathway activation in these cells. Western blot analyses
of JNK and c-Jun using phospho-specific antibodies reveal
that JNK and subsequent c-Jun phosphorylation occur hours
before the initiation of apoptosis, reflected morphologically
by neurite retraction and fragmentation, cell-body shrinkage
and chromatin fragmentation. Immunocytochemistry using
the same antibodies shows that phospho-JNK are localized
in the neurites of control neurons and translocate to the
nucleus where phospho-c-Jun concurrently appears upon
ceramide-induced apoptosis. To determine if ceramide-induced
c-Jun activation is responsible for the induction of the
apoptotic program, we performed transient transfections of a
dominant negative form of c-Jun, truncated in its transactivation
region. Our results show that DNc-Jun partially protects
cortical neurons from ceramide-induced apoptosis.
Treatment of dominant negative c-Jun-expressing neurons
with the pharmacological inhibitor of p38 kinase, SB203580,
completely blocked neuronal death. Thus our data show that
p38 and JNK/c-Jun pathways cooperate to induce neuronal
Actions (login required)