Furthermore, once activated, the mitochondrial death cascade then causes elimination of Mcl-1, as this anti-apoptotic Bcl-2 protein was shown to become proteolytically inactivated during PI-induced apoptosis in a caspase-3-dependent 143901-35-3 manner. Intriguingly, JNK12/2 mice are highly susceptible to DMBA/PMA-induced skin tumor formation when compared to similar treated wild type mice. As both JNKs and the human Noxa orthologue PMAIP1 can be strongly activated by phorbol esters, it is tempting to speculate that this tumor suppressive function of JNK1 depends on the induction of Noxa. As, however, JNKs including JNK1 are able to exert also oncogenic functions, that were particularly evident in the development of human hepatocellular carcinoma, it is highly likely that JNK1 mediates its versatile functions strictly in a cell type-dependent manner. Besides being reported as a PMA-inducible protein, Noxa was originally identified as a p53-induced stress response gene, but is now known to be regulated by an array of different transcription factors independently of p53. However, although several transcription factors known to participate in JNK signaling and diverse apoptosis pathways, and that were even shown to constitute prominent targets of the proteasome, none of those examined here including c-Jun, c-Myc, Hif1a, ATF3, ATF4 and GR appear to be involved in the herein observed JNK1/2- dependent opposite regulation of Noxa. A participation of p53 cannot be completely ruled out, as a few MEF lines studied here may harbor p53 mutations. Perhaps most unexpected was our finding that even the knockdown of c-Myc, a transcription factor that was recently demonstrated to transcriptionally upregulate Noxa during bortezomib-induced apoptosis, did not affect Noxa expression despite the observed protection of JNK22/2 cells from PI-induced apoptosis. Particularly with regard to the fact that JNKs phosphorylate and thereby regulate the apoptotic function of c-Myc, its previous identification as a potent Noxa inducer upon PI treatment provided strong evidence for the existence of a JNK-Myc-Noxa axis, at least in 474645-27-7 melanoma cells. As the thereby identified c-Myc binding site in the Noxa promoter is conserved among human, mouse and rat, it is presently unknow
