the practical linkage between activation of p53 and JNK signaling has not been elucidated in MM cells induced by p53 reactivating agencies such as RITA. Here we provide the first line of proof that the activation of JNK includes a crucial role for successful induction of apoptosis by pharmacologically triggered buy Ibrutinib p53. Off note, the activation of JNK signaling in MM cells was found to be selective for RITA in comparison with other nongenotoxic or genotoxic drugs. In addition, the JNK activation by RITA seems to be more efficient in MM cells when compared with other tumor cell types. Furthermore, we found that induction of p53 is independent of activation of JNK signaling, because RITA induces phosphorylation of c Jun in cells where p53 was mutated or null. The inhibition of p53 activation upon silencing of JNK implies that induction of p53 signaling occurs downstream of JNK which will be contrary to the previous transfer RNA (tRNA) studies where JNK activation was described as a downstream celebration of p53 activation related to activation of EGR1 and p73. Yet another important factor of our study is the fact that inhibition of activation of p53 transcriptional targets by PFTa or p53 siRNA led to inhibition of phosphorylation of c Jun. These results show the establishment of a positive feedback loop between p53 and JNK potentiating the apoptosis induction by RITA. We’ve demonstrated that activation of JNK is playing an apoptotic role in MM cells induced by RITA, which can be consistent with a previous statement showing the necessity of JNK activation JNK for your stabilization of p53 and enhancement of p53 trans activation by abrogating MDM2 association in p53 null fibroblast. Nevertheless, depending on the mobile context, c Jun may play a survival role. These opposite effects have previously been reported for d t and Jun catenin, a vital part of the Wnt signaling pathway as well as for p53 mediated JNK activation. Activation of JNK in these studies was called just a downstream function of p53 and inhibition of endogenous JNK activity resulted BAY 11-7082 BAY 11-7821 in a growth of apoptosis in response to nocodazole treatment of human colon carcinoma cells harboring wild-type p53 in the latter studies. Depending on our results we suggest a schematic model showing a novel mechanism of p53 dependent JNK mediated induction of apoptosis by RITA. Stimulation of MM cells by RITA leads to activation of JNK through JNK stream and phosphorylation of c Jun, which causes p53 accumulation. Triggered p53 subsequently might increase JNK signaling through a positive feedback loop between p53 and JNK. JNK activation has previously been shown to phosphorylate p53 at its N terminal activation loop. We noticed activation of JNK in the lack of phosphorylation of p53 in RITA induced MM cells. Consequently, further study is likely to be necessary to understand whether JNK can specifically activate p53 in MM cells.