Ceramide is an important regulatory molecule implicated in a variety of biological processes in response to stress and cytokines. To understand the signal transduction pathway of ceramide to the nucleus, in the present study, we examined whether C2-ceramide, a cell permeable ceramide, activates c-fos serum response element (SRE). Treatment of Rat-2 fibroblast cells with C2-ceramide caused the stimulation of c-fos SRE-dependent reporter gene activity in a dose- and time-dependent manner by transient transfection analysis. Next, we examined the role of Rho family GTPases in the ceramide-induced signalling to SRE activation. By reporter gene analysis following transient transfections with various plasmids expressing a dominant negative mutant form of Cdc42, Rac1 or RhoA, C2-ceramide-induced SRE activation was shown to be selectively repressed by pEXV-RacN17 encoding a dominant negative mutant of Rac1, suggesting that Rac activity is essential for the signalling cascade of ceramide to the nucleus. In a further study to analyse the downstream mediator of Rac in the ceramide-signalling pathway, we observed that either pretreatment with mepacrine, a potent and specific inhibitor of phospholipase A2, or co-transfection with antisense cytosolic phospholipase A2 (cPLA2) oligonucleotide repressed the C2-ceramide-induced SRE activation selectively, implying a critical role of cPLA2 in C2-ceramide-induced signalling to nucleus. Consistent with these results, the translocation of cPLA2 protein as well as the release of arachidonic acid, a principal product of phospholipase A2, was rapidly induced by the addition of C2-ceramide in a Rac-dependent manner. Together, our findings suggest the critical role of ‘Rac and subsequent activation of phospholipase A2’ in ceramide-signalling to nucleus.
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March 1998
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Research Article|
March 01 1998
Exogenous C2-ceramide activates c-fos serum response element via Rac-dependent signalling pathway Available to Purchase
Byung-Chul KIM;
Byung-Chul KIM
1Laboratory of Molecular & Cellular Genetics, Institute of Environment and Life Science, Hallym University, Chun-Cheon, Kangwon-do, South Korea #200-702
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Jae-Hong KIM
Jae-Hong KIM
1
1Laboratory of Molecular & Cellular Genetics, Institute of Environment and Life Science, Hallym University, Chun-Cheon, Kangwon-do, South Korea #200-702
1To whom correspondence should be addressed.
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Publisher: Portland Press Ltd
Received:
June 17 1997
Revision Received:
November 24 1997
Accepted:
December 03 1997
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1998
1998
Biochem J (1998) 330 (2): 1009–1014.
Article history
Received:
June 17 1997
Revision Received:
November 24 1997
Accepted:
December 03 1997
Citation
Byung-Chul KIM, Jae-Hong KIM; Exogenous C2-ceramide activates c-fos serum response element via Rac-dependent signalling pathway. Biochem J 1 March 1998; 330 (2): 1009–1014. doi: https://doi.org/10.1042/bj3301009
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