EARLY ACTIVATION OF C-JUN N-TERMINAL KINASE AND P38 KINASE REGULATE CELL-SURVIVAL IN RESPONSE TO TUMOR-NECROSIS-FACTOR-ALPHA

Fas ligand and tumor necrosis factor alpha (TNF) bind to members of th e TNF receptor superfamily. Stimulation by Fas ligand results in apopt osis, whereas TNF induces multiple effects including proliferation, di fferentiation, and apoptosis. Activation of the c-Jun N-terminal kinas e (JNK) and p38 kinase pathways is common to Fas and TNF signaling; ho wever, their role in apoptosis is controversial. Fas receptor cross-li nking induces apoptosis in the absence of actinomycin D and activates JNK in a caspase-dependent manner. In contrast, TNF requires actinomyc in D for apoptosis and activates JNK and p38 kinase with biphasic kine tics. The first phase is transient, precedes ap opto sis, and is caspa se-independent, whereas the second phase is coincident with apoptosis and is caspase-dependent. Inhibition of early TNF-induced JNK and p38 kinases using MKK4/MKK6 mutants or the p38 inhibitor SB203580 increase s TNF-induced apoptosis, whereas expression of wild type MKK4/MKK6 enh ances survival. In contrast, the Mek inhibitor PD098059 has no effect on survival. These results demonstrate that early activation of p38 ki nase (but not Mek) are necessary to protect cells from TNF-mediated cy totoxicity. Thus, early stress kinase activation initiated by TNF play s a key role in regulating apoptosis.