PMC:3585731 / 2079-4318 JSONTXT

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Several recent studies [10], [11], [12], [13], [14] have suggested that JNK kinase activation plays an important role during necroptosis in L929 cells downstream from RIP1 kinase. For example, the transcription factor c-Jun, a key cellular target of JNK activity, was one of the hits in the genome wide siRNA screen [10]. Activation of JNK in L929 cells has been linked to autocrine TNFα synthesis, activation of oxidative stress and induction of autophagy, all of which contribute to necroptosis. Importantly, RIP1 kinase dependent activation of JNK and TNFα production has recently been described to be independent of its role in necroptosis [15]. Curiously, Akt kinase, a key pro-survival molecule and a well-established inhibitor of apoptotic cell death, has also recently been linked to necroptosis in L929 cells [16], where insulin-dependent activation of Akt was suggested to promote necroptosis by suppressing autophagy. This conclusion was unexpected, since several reports from different groups, including ours, have established that autophagy promotes, rather than suppresses, zVAD.fmk-induced necroptosis in L929 cells [11], [14], [17]. This raised the possibility that Akt controls more general mechanisms that contribute to the execution of necroptosis. Furthermore, the key question of whether insulin-dependent Akt activity solely provides an environment conducive for necroptosis or if Akt activation is an intrinsic component of necroptosis signaling that is linked to RIP1 kinase has not been 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