zVAD-induced necroptosis in L929 cells depends on autocrine production of TNFα mediated by the PKC-MAPKs-AP-1 pathway.

摘要: It is intriguing that some pan-caspase inhibitors such as zVAD-fmk (zVAD) are capable of inducing necrotic cell death in a selected group cells. As earlier reports from our laboratory have ruled out the original notion zVAD-induced necrosis mouse fibrosarcoma L929 cells was autophagic death, main objective this study thus to determine underlying mechanism form death. In study, we provided clear evidence necroptosis and dependent on autocrine production tumor factor-α (TNFα) at transcriptional level. More importantly, identified activating protein-1 (AP-1), but not nuclear factor κ-B, transcription controlling TNFα transcription. Moreover, zVAD able activate AP-1 through activation two upstream mitogen-activated kinases (MAPKs), c-Jun N-terminal kinase extracellular signal-regulated kinase. Finally, found protein C important signaling molecule mediating MAPKs AP-1, subsequent Data reveal molecular mechanisms necroptosis, an programmed with increasing understanding its biological significance health diseases.