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JCS ePress online publication date 30 Nov 2004
doi: 10.1242/jcs.01573

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Research Article

p38{alpha}, but not p38{beta}, inhibits the phosphorylation and presence of c-FLIPS in DISC to potentiate Fas-mediated caspase-8 activation and type I apoptotic signaling


Leon Tourian Jr, Hong Zhao, and Coimbatore B. Srikant*
* Author for correspondence (e-mail: coimbatore.srikant{at}mcgill.ca)

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{alpha}) or inhibit (p38{beta}) apoptosis are both suppressed by PD169316, we investigated their regulatory involvement in Fas-signaling. We report here, that p38{alpha}, but not p38{beta}, exerts its proapoptotic effect by inhibiting the phosphorylation and presence of c-FLIPS, but not c-FLIPL, 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{alpha} and was attenuated by its inactive mutant (p38{alpha}-AGF) or by translational silencing. By contrast, type II signaling was facilitated by p38{alpha}-dependent mitochondrial presence of tBid and inhibition of Bcl-2 (Ser70) phosphorylation as well as by p38{alpha}/{beta}-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{alpha} on DISC and the downstream effects of both p38{alpha} and p38{beta}. These data underscore the need to reassess the findings obtained with pan-p38 inhibitors and suggest that activation of p38{alpha} coupled with targeted inhibition of p38{beta} and JNK1/2 should optimally sensitize tumor cells to Fas-mediated apoptosis.
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