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First published online 30 November 2004
doi: 10.1242/jcs.01573

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p38, but not p38ß, inhibits the phosphorylation and presence of c-FLIP_S in DISC to potentiate Fas-mediated caspase-8 activation and type I apoptotic signaling

Fraser Laboratories, Department of Medicine, McGill University Health Centre and Royal Victoria Hospital, Montreal, Quebec, H3A 1A1, Canada

^* Author for correspondence (e-mail: coimbatore.srikant{at}mcgill.ca)

Accepted 30 September 2004

Pharmacological inhibitors of JNK (SP600125) and p38 (PD169316) sensitize tumor cells to Fas-mediated apoptosis. PD169316 is less potent than SP600125 and diminishes its effect when present together. Because the p38 isoforms that promote (p38) or inhibit (p38ß) apoptosis are both suppressed by PD169316, we investigated their regulatory involvement in Fas-signaling. We report here, that p38, but not p38ß, exerts its proapoptotic effect by inhibiting the phosphorylation and presence of c-FLIP_S, but not c-FLIP_L, in the DISC to promote caspase-8 activation and type I signaling in Fas-activated Jurkat cells. Its effect was enhanced by enforced expression of Flag-tagged p38 and was attenuated by its inactive mutant (p38-AGF) or by translational silencing. By contrast, type II signaling was facilitated by p38-dependent mitochondrial presence of tBid and inhibition of Bcl-2 (Ser70) phosphorylation as well as by p38/ß-dependent mitochondrial localization of Bax and inhibition of phosphorylation of Bad (Ser112/Ser155). Potentiation of Fas-mediated apoptosis by the inhibition of JNK1/2 correlated with the loss of Bad (Ser136) phosphorylation and was dependent on the stimulatory effect of p38 on DISC and the downstream effects of both p38 and p38ß. These data underscore the need to reassess the findings obtained with pan-p38 inhibitors and suggest that activation of p38 coupled with targeted inhibition of p38ß and JNK1/2 should optimally sensitize tumor cells to Fas-mediated apoptosis.

Key words: DISC, c-FLIP, JNK, Mitochondria, Caspase

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