Fas- or ceramide-induced apoptosis is mediated by a rad-regulated activation of jun N-terminal kinase p38 kinases and GADD153

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, Rad, 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.