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


Willaime-Morawek, S., Brami-Cherrier, K., Mariani, J., Caboche, J. and Brugg, B. (2003) C-Jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis. Neuroscience, 119, (2), 387-397. (doi:10.1016/S0306-4522(02)00996-X).

Download

[img] PDF
Download (526Kb)

Description/Abstract

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
apoptosis.

Item Type: Article
ISSNs: 0306-4522 (print)
Related URLs:
Keywords: primary cultures, SAPK, serum withdrawal, neuronal death
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Divisions: University Structure - Pre August 2011 > School of Medicine > Clinical Neurosciences
ePrint ID: 66392
Date Deposited: 10 Jun 2009
Last Modified: 27 Mar 2014 18:47
URI: http://eprints.soton.ac.uk/id/eprint/66392

Actions (login required)

View Item View Item

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics