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Ceramide-induced apoptosis in cortical neurons is mediated by an increase in p38 phosphorylation and not by the decrease in ERK phosphorylation

Ceramide-induced apoptosis in cortical neurons is mediated by an increase in p38 phosphorylation and not by the decrease in ERK phosphorylation
Ceramide-induced apoptosis in cortical neurons is mediated by an increase in p38 phosphorylation and not by the decrease in ERK phosphorylation
Ceramide, the central molecule of the sphingomyelin pathway, serves as a second messenger for cellular functions ranging from proliferation and differentiation to growth arrest and apoptosis. In this study we show that c2-ceramide induces apoptosis in primary cortical neuron cultures and that this effect correlates with differential modulation of mitogen-activated protein kinase (MAPK) cascades. Phosphorylation of extracellular signal-regulated kinases (ERKs) and their upstream activators MAPK kinases (MEKs), as measured by immunoblotting is rapidly decreased by c2-ceramide. However, the MEK inhibitor PD98059 alone does not induce apoptosis and in combination with c2-ceramide it does not modify c2-ceramide-induced apoptosis. Treatment with c2-ceramide increases p38 and c-Jun N-terminal kinase (JNK) phosphorylation before and during caspase-3 activation. The p38 inhibitor SB203580 partially protects cortical neurons against c2-ceramide-induced apoptosis, implicating the p38 pathway in this process. The c2-ceramide treatment also increases levels of c-jun, c-fos and p53 mRNA in primary cortical neuron cultures, but this is independent of p38 activation. Our study further elucidates the time-courses of MAPK cascade modulation, and of c-jun, cfos and p53 activation during c2-ceramide-induced neuronal apoptosis. It reveals that one of the activated kinases, p38, is necessary for this apoptosis.
c-Fos, c-Jun, JNKs/ SAPKs, MAPK, p53, primary cultures
0953-816X
2037-2046
Willaime, S.
24a2981f-aa9e-4bf6-ad12-2ccf6b49f1c0
Vanhoutte, P.
f4e528c7-3a90-4999-8eab-45cdfac9d6dd
Caboche, J.
071c14c4-71c6-435d-9725-8bde4e2f6447
Lemaigre-Dubreuil, Y.
1395e8d7-f2ca-43e8-91d4-4cb9fde9e35c
Mariani, J.
d41a573a-a1ac-4c1b-b8d3-d97fad4756d1
Brugg, B.
47c3b9cc-b1ab-4a9c-addd-a100221e513a
Willaime, S.
24a2981f-aa9e-4bf6-ad12-2ccf6b49f1c0
Vanhoutte, P.
f4e528c7-3a90-4999-8eab-45cdfac9d6dd
Caboche, J.
071c14c4-71c6-435d-9725-8bde4e2f6447
Lemaigre-Dubreuil, Y.
1395e8d7-f2ca-43e8-91d4-4cb9fde9e35c
Mariani, J.
d41a573a-a1ac-4c1b-b8d3-d97fad4756d1
Brugg, B.
47c3b9cc-b1ab-4a9c-addd-a100221e513a

Willaime, S., Vanhoutte, P., Caboche, J., Lemaigre-Dubreuil, Y., Mariani, J. and Brugg, B. (2001) Ceramide-induced apoptosis in cortical neurons is mediated by an increase in p38 phosphorylation and not by the decrease in ERK phosphorylation. European Journal of Neuroscience, 13 (11), 2037-2046. (doi:10.1046/j.0953-816x.2001.01581.x).

Record type: Article

Abstract

Ceramide, the central molecule of the sphingomyelin pathway, serves as a second messenger for cellular functions ranging from proliferation and differentiation to growth arrest and apoptosis. In this study we show that c2-ceramide induces apoptosis in primary cortical neuron cultures and that this effect correlates with differential modulation of mitogen-activated protein kinase (MAPK) cascades. Phosphorylation of extracellular signal-regulated kinases (ERKs) and their upstream activators MAPK kinases (MEKs), as measured by immunoblotting is rapidly decreased by c2-ceramide. However, the MEK inhibitor PD98059 alone does not induce apoptosis and in combination with c2-ceramide it does not modify c2-ceramide-induced apoptosis. Treatment with c2-ceramide increases p38 and c-Jun N-terminal kinase (JNK) phosphorylation before and during caspase-3 activation. The p38 inhibitor SB203580 partially protects cortical neurons against c2-ceramide-induced apoptosis, implicating the p38 pathway in this process. The c2-ceramide treatment also increases levels of c-jun, c-fos and p53 mRNA in primary cortical neuron cultures, but this is independent of p38 activation. Our study further elucidates the time-courses of MAPK cascade modulation, and of c-jun, cfos and p53 activation during c2-ceramide-induced neuronal apoptosis. It reveals that one of the activated kinases, p38, is necessary for this apoptosis.

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Published date: February 2001
Keywords: c-Fos, c-Jun, JNKs/ SAPKs, MAPK, p53, primary cultures

Identifiers

Local EPrints ID: 66391
URI: http://eprints.soton.ac.uk/id/eprint/66391
ISSN: 0953-816X
PURE UUID: 9354faaf-cc89-4191-b128-4e0ae3e760d1
ORCID for S. Willaime: ORCID iD orcid.org/0000-0002-1121-6419

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Date deposited: 10 Jun 2009
Last modified: 14 Mar 2024 02:53

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Contributors

Author: S. Willaime ORCID iD
Author: P. Vanhoutte
Author: J. Caboche
Author: Y. Lemaigre-Dubreuil
Author: J. Mariani
Author: B. Brugg

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