MITOGEN-ACTIVATED PROTEIN KINASE-MEDIATED FAS APOPTOTIC SIGNALING PATHWAY

Ligation of the cell surface receptor Fas/APO-1 (CD95) by its specific ligand or by anti-Fas antibodies rapidly induces apoptosis in suscept ible cells, To characterize the molecular events involved in Fas-induc ed apoptosis, we examined the contribution of two subgroups of the mit ogen-activated protein (MAP) kinase family, the Jun kinases or stress- activated protein kinases (JNKs/SAPKs) and the extracellular signal-re gulated kinases (ERKs), in a Fas-sensitive neuroblastoma cell line. He re we show that both JNK and ERK protein kinases were activated upon F as crosslinking through a Ras-dependent mechanism, Interference with e ither the JNK or ERK pathway by ectopic expression of dominant-interfe ring mutant proteins blocked Fas-mediated apoptosis, ERK activation wa s transient and associated with induced expression of the Fas receptor , In contrast, JNK activation was sustained and correlated with the on set of apoptosis, These data indicate that the ERK and the JNK groups of MAP kinases cooperate in the induction of cell death by Fas, Inhibi tion of Fas killing by an interleukin Ip-converting enzyme (ICE)-like protease inhibitor peptide did not modify Fas-induced JNK activation u pon Fas ligation, In contrast, changes in Bcl-2 level due to expressio n of sense and antisense vectors influenced the sensitivity to Fas kil ling and Fas-induced JNK activation.