ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis

Apoptosis signal-regulating kinase (ASK) 1 is activated in response to vari ous cytotoxic stresses including TNF, Fas and reactive oxygen species (ROS) such as H2O2 and activates c-Jun NH2-terminal kinase (JNK) and p38. Howeve r, the roles of JNK and p38 signaling pathways during apoptosis have been c ontroversial. Here we show that by deleting ASK1 in mice, TNF- and H2O2-ind uced sustained activations of INK and p38 are lost in ASK1(-/-) embryonic f ibroblasts, and that ASK1(-/-) cells are resistant to TNF- and H2O2-induced apoptosis. TNF- but not Fas-induced apoptosis requires ROS-dependent activ ation of ASK1-JNK/p38 pathways. Thus, ASK1 is selectively required for TNF- and oxidative stress-induced sustained activations of JNK/p38 and apoptosi s.