Fas- or Ceramide-induced Apoptosis Is Mediated by a Rac1-regulated Activation of Jun N-terminal Kinase/p38 Kinases and GADD153

Abstract

In the present study, we show that Fas receptor ligation or cellular treatment with synthetic C 6 -ceramide results in activation or phosphorylation, respectively, of the small G-protein Rac1, Jun N-terminal kinase (JNK)/ p38 kinases (p38-K), and the transcription factor GADD153. A signaling cascade from the Fas receptor via ceramide, Ras, Rac1, and JNK/p38-K to GADD153 is demonstrated employing transfection of transdominant inhibitory N17Ras, N17Rac1, c-Jun, or treatment with a specific p38-K inhibitor. The critical function of this signaling cascade is indicated by prevention of Fas-or C 6 -ceramide-induced apoptosis after inhibition of Ras, Rac1, or JNK/p38-K.

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

“…Several intermediate kinases described in other cellular systems may be involved in this process in neurons, including the small G-protein Rac1 (Brenner et al, 1997), the MAP kinase TGF␤-activating kinase 1 (Schirakabe et al, 1997); the MAP 3 kinase 1 (Takekawa et al, 1997) or the apoptosis signal-regulated kinase 1 (Chen et al, 1999). Further investigations will help to determine how ceramide and serum withdrawal induce the JNK pathway in neurons.…”

“…Thus, our data further demonstrate that p38 kinase and JNK/c-Jun act in parallel to induce neuronal apoptosis by ceramide. The pro-apoptotic action of p38 in ceramide-induced apoptosis may be mediated by apoptotic effectors: Bax translocation from the cytosol to the mitochondria is dependent upon p38 (Ghatan et al, 2000); Bid is cleaved upon p38 activation and leads to mitochondrial dysfunction (Zhuang et al, 2000); Fas-ligand expression is regulated by p38 and is pro-apoptotic (Zhang et al, 2000); GADD153/CHOP activation is controlled by p38 and is involved in ceramide-induced apoptosis (Brenner et al, 1997). The pro-apoptotic action of JNK/c-Jun in ceramideinduced apoptosis may be mediated by apoptotic effectors such as Fas-ligand which expression is also regulated by JNK (Herdegen et al, 1998;Morishima et al, 2001), since the Fas-ligand promoter contains an AP-1 site that enables the promoter to be activated by the JNK pathway.…”

Ceramide: A common pathway for atherosclerosis?

“…Some of these roles are directly involved in the molecular mechanisms of cardiovascular disease. Ceramide pathway has been involved in the activation of several signaling molecules including protein phosphatase, protein kinase C, small G-protein Ras, Rac1, Rho and Jun N-terminal kinase (JNK)/p38 kinases (p38-K) [90][91][92]. Stimuli of ceramide production and effects of ceramides are listed in Table 1.…”

Stress signals for apoptosis: ceramide and c-Jun kinase

“…The evidence that the JNK pathway is pro-apoptotic derives from studies that show that these kinases are activated rapidly in cells destined to undergo an apoptotic response, that their overexpression results in apoptosis in some cells, that anti-sense inhibition or the use of dominant negative constructs attenuates the apoptotic response, and in a recent publication by the use of a knock-out mouse Brenner et al, 1997;Butter®eld et al, 1997;Cardone et al, 1997;Chen et al, 1996a,b;Chuang et al, 1997;Frisch et al, 1996;Goillot et al, 1997;Seimiya et al, 1997;Verheij et al, 1996;Xia et al, 1995;Yang et al, 1997a;Zanke et al, 1996). In the latter studies, in mice de®cient in JNK3, which is restricted to the brain, there was a reduction in seizure activity and hippocampal apoptosis in response to the excitotoxic glutamate-receptor agonist kainic acid (Yang et al, 1997a).…”