FAS-INDUCED 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 t reatment with synthetic C-6-ceramide results in activation or phosphor ylation, respectively, of the small G-protein Rac1, Jun N-terminal kin ase (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 transdo minant inhibitory N17Ras, N17Rac1, c-Jun, or treatment with a specific p38-K inhibitor. The critical function of this signaling cascade is i ndicated by prevention of Fas-or C-6-ceramide-induced apoptosis after inhibition of Ras,Rac1, or JNK/p38-K.