CD95-induced JNK activation signals are transmitted by the death-inducing signaling complex (DISC), but not by DAXX

Here we investigated CD95-mediated JNK activation pathways and their physio logical relevance by employing a variety of cell lines with deficiencies in individual signal transmitting proteins. JNK activation was completely dep endent on the activation of caspases in type I and type II cells, as reveal ed by the inhibitory effects of the caspase inhibitors zVAD-fmk or the cowp oxvirus-encoded CrmA protein. Jurkat cells deficient in caspase-8 or expres sing a dominant negative (DN) form of FADD were unable to induce JNK in res ponse to CD95 ligation, indicating that these death-inducing signaling comp lex (DISC) proteins are required for signal transmission, Activation of cas pases, JNK and apoptosis occurred with a markedly slower kinetics in cells expressing a DN version of ASK1, revealing an important contribution of ASK 1 for these processes, A C-terminally truncated version of Daxx impaired CD 95-mediated apoptosis without affecting the INK signal. DN forms of FADD, M KK4 and MKK7 completely inhibited CD95-mediated INK activation but remained without impact on cell killing, indicating that JNK activation is not requ ired for the execution process of CD95-mediated cell killing. (C) 2001 Wile y-Liss, Inc.