Involvement of JNK in the regulation of autophagic cell death

Abstract

Programmed cell death is a crucial process in the normal development and physiology of metazoans, and it can be divided into several categories that include type I death (apoptosis) and type II death (autophagic cell death). The Bcl-2 family proteins are well-characterized regulators of apoptosis, among which multidomain pro-apoptotic members (such as Bax and Bak) function as a mitochondrial gateway at which various apoptotic signals converge. Although embryonic fibroblasts from Bax/Bak doubleknockout (DKO) mice are resistant to apoptosis, we have previously reported that these cells still die by autophagy in response to various death stimuli. In this study, we found that jun N-terminal kinase (JNK) was activated in etoposide-and staurosporine-treated, but not serumstarved, Bax/Bak DKO cells, and that autophagic cell death was suppressed by the addition of a JNK inhibitor and by a dominant-negative mutant of JNK. Studies with sek1À/À cells revealed that disruption of JNK prevented the induction of autophagic cell death. Coactivation of JNK and autophagy induced autophagic cell death. Activation of JNK occurred downstream of the induction of autophagy, and was dependent on the autophagic process. These results indicate that JNK activation is crucial for the autophagic death of Bax/ Bak DKO cells.

JNK regulates FoxO-dependent autophagy in neurons

“…3) was unexpected, because studies of nonneuronal cells have implicated JNK in the induction of autophagy (Yu et al 2004;Ogata et al 2006;Wei et al 2008) or as an effector of autophagy-associated cell death (Yu et al 2004;Shimizu et al 2010). Indeed, we found that autophagy caused by serum withdrawal was compromised in compound mutant fibroblasts that lack JNK expression (Supplemental Fig.…”

Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study

“…Indeed, there are no or few convincing examples in which specific inhibition of autophagy by knockout or knockdown of essential autophagy-relevant genes (the ATG gene) would fully inhibit cell death induced by specific stressors or pharmacological agents (Shimizu et al, 2004(Shimizu et al, , 2010Berry and Baehrecke, 2007;Samara et al, 2008;Turcotte et al, 2008). Rather, autophagy is usually a self-limited process that protects cells from death by multiple mechanisms, including improved maintenance of bioenergetic homeostasis, recycling of misfolded and aggregate prone proteins, and removal of damaged organelles such as uncoupled or permeabilized mitochondria Mizushima et al, 2008).…”

Autophagic Cell Death and Cancer Chemotherapeutics

“…These mechanisms may be cell-and stimulus-type specifi c; however, we believe that it is reasonable to conclude that the failure of autophagic cell death is one of the most crucial mechanisms involved in tumorigenesis because autophagic cell death occurs in normal cells (e.g., fi broblasts or thymocytes) but not in most cancer cells. Furthermore, in some cancer cells, the magnitude of JNK activation, which is a crucial factor for autophagic cell death, is signifi cantly lower compared with that in normal cells after exposure to apoptotic stimuli [ 21 ]. In these cancer cells, the JNK activity level may not reach the threshold level required to induce autophagic cell death.…”

“…Several mechanisms may explain how tumorigenesis is mediated by the failure of cells to undergo autophagy: (1) accumulation of p62, a substrate of autophagy, leads to NF-κB activation [ 19 ]; (2) accumulation of p62 stabilizes Nrf2, which makes tumor cells resistant to hypoxic stress [ 20 ]; (3) retention of damaged organelles, including mitochondria, increases the level of active oxygen species and increases the mutation rate; and (4) defective elimination of cancer cells due to the loss of autophagic cell death [ 21 ]. These mechanisms may be cell-and stimulus-type specifi c; however, we believe that it is reasonable to conclude that the failure of autophagic cell death is one of the most crucial mechanisms involved in tumorigenesis because autophagic cell death occurs in normal cells (e.g., fi broblasts or thymocytes) but not in most cancer cells.…”