Figure 24

ROS-dependent sustained activation of JNK isoforms as a crucial event in inducing cell death. ROS-mediated sustained activation of JNK isoforms is likely to rely on inhibition of JNK phosphatases and/or activation of the upstream kinase ASK-1, finally resulting in mitochondrial outer membrane permeabilization. To explain this later, crucial event, the following hypotheses have been proposed: a) JNK may, in a caspase-independent way that has still not been characterized, promote the cleavage of the BH3 domain of Bid, resulting in the production of jBid, which should operate in a pro-apoptotic way similarly to tBid [209]; b) JNK may favour apoptosis by increasing proteasomal degradation of cFLIP (the inhibitor of pro-caspase 8/10 activation) by activating the ubiquitin ligase Itch [199]; c) by pro-apoptotic modifications of proteins belonging to the Bcl-2 family, such as Bax or Bcl-XL [187, 194].