INDUCTION OF APOPTOSIS BY SB202190 THROUGH INHIBITION OF P38-BETA MITOGEN-ACTIVATED PROTEIN-KINASE

p38, a subfamily of the mitogen-activated protein kinase, regulates ge ne expression in response to various extracellular stimuli. The pyridi nyl imidazoles like SB202190 are specific inhibitors of p38 alpha and p38 beta and have been widely used in investigation of the biological functions of p38. Here we show that SB202190 by itself was sufficient to induce cell death, with typical apoptotic features such as nucleus condensation and intranucleosomal DNA fragmentation. SB202190 stimulat ed the activity of CPP32-like caspases, and its apoptotic effect was c ompletely blocked by the protease inhibitor benzyloxycarbonyl-Val-Ala- Asp-fluoromethyl ketone and expression of bcl-2. In addition, SB202190 was able to potentiate apoptosis induced by Fas(APO-1) ligation or UV irradiation. Expression of p38 beta attenuated the apoptotic effect o f SB202190 and the cell death induced by Fas ligation and UV irradiati on. In contrast, expression of p38 alpha induced cell death mildly. Th ese results indicate that SB202190 induces apoptosis through activatio n of CPP32-like caspases and suggest that distinct members of the p38 subfamily of mitogen-activated protein kinase have different functions in apoptosis.