The recruitment of Fas-associated death domain/caspase-8 in Ras-induced apoptosis

Oncogenic Ras induces cells to undergo apoptosis after inhibition of protei n kinase C (PKC) activity. The integration of differential signaling pathwa ys is required for full execution of apoptosin. In this study, we used Jurk at as well as Fas/FADD-defective cell lines expressing v-ras to determine t he upstream elements required for activation of the caspase cascade in PKC/ Ras-mediated apoptosis. During this Has-induced apoptotic process, caspase- 8 was activated, possibly through its binding to Fas-associated death domai n (FADD), in jurkat/ras and Jurkat/Fas(m)/ras cells but not in Jurkat/FADD( m)/ras cells. c-Jun NH2-terminal kinase (JNK) was activated in all three ce ll lines expressing ras in response to apoptotic stimulation. Suppression o f JNK by dn-JNK1 blocked the interaction of FADD and caspase-8 and partiall y protected Jurkat/ras and Jurkat/Fas(m)/ras cells from apoptosis. However, dn-JNK1 had no effect on PKC/Ras-induced apoptosis in Jurkat/FADD(m)/ras c ells. The results indicate that FADD/caspase-8 signaling is involved in PKC /Ras-mediated apoptosis, and JNK may be an upstream effector of caspase act ivation.