C‐jun N‐terminal kinase regulates the interaction between 14‐3‐3 and Bad in ethanol‐induced cell death

Abstract

Activation of the c-jun N-terminal kinase (JNK) is known to be an important step during ethanol-induced cell death, but it has yet to be identified how JNK regulates apoptosis. Therefore, we investigated the mechanism by which JNK induces cell death following ethanol treatment. Ethanol (6 g/kg, 20% in saline) was administered subcutaneously to postnatal 7 day rat pups. Twelve hours after the first ethanol administration, rat pups were decapitated, and extracts of total protein from cerebral cortices were prepared. Ethanol exposure induced phosphorylation of JNK but did not affect the expression levels of pro- and antiapoptotic proteins. Furthermore, interactions of phospho-JNK (p-JNK) with 14-3-3 as well as with Bad were enhanced in the cerebral cortices of ethanol-treated rats. Pretreatment with JNK inhibitor (SP600125) of SH-SY5Y cells inhibited JNK phosphorylation and interaction between p-JNK and 14-3-3 resulting from ethanol. Furthermore, 14-3-3 interaction with Bad was diminished in the cerebral cortices of ethanol-treated rats. These findings suggest that JNK induces Bad release from 14-3-3 by inhibiting their interaction. After this event, Bad binds to Bcl-xL, releasing Bax from Bcl-xL and leading to cell death. We hypothesize that JNK may play an important role during ethanol-induced cell death via the inhibition of antiapoptotic function of 14-3-3 as well as activation of proapoptotic function of Bad.

Long-term ethanol exposure causes human liver cancer cells to become resistant to mitomycin C treatment through the inactivation of bad-mediated apoptosis

“…Subsequently, Bad dimerizes with Bcl-xL, triggering Bax release from Bcl-xL, which leads to the translocation of Bax to the mitochondria, cytochrome c release, and downstream apoptotic cascade activation [45]. Similar results also demonstrated that acute ethanol exposure of rats at a more vulnerable age decreased the formation of Bad-14-3-3 complexes [46]. All of these results imply that the sequestration binding of Bad to 14-3-3 plays a role in the hepatocellular carcinogenic process in response to ethanol consumption ( Figure 4).…”

Rutin attenuates isoflurane-induced neuroapoptosis via modulating JNK and p38 MAPK pathways in the hippocampi of neonatal rats

“…The JNK signalling pathway is involved in neuronal apoptosis triggered by several brain injury stimuli, such as ischemic reperfusion injury (43)(44)(45). Previous studies have demonstrated that the activation of JNK signalling is involved in isoflurane-induced neuronal apoptosis (7).…”

“…Activated JNK phosphorylates a nuclear substrate, the transcription factor c-Jun, which results in an increase of activator protein-1 transcription activity to modulate the transcription of genes associated with apoptosis. By contrast, activated JNK regulates the activation of non-nuclear substrates, including Bcl-2 family members (43,45).…”

Neuroprotective effects of pterostilbene against isoflurane-induced apoptosis through regulating the JNK and PI3K/Akt pathway in neonatal rats

“…The JNK signalling pathway is implicated in neuronal apoptosis triggered by several brain injury stimuli, such as ischemia/reperfusion and ethanol (Guan et al, 2006;Han et al, 2008;Fan et al, 2010). The JNK pathways include nuclear and non-nuclear pathways (Han et al, 2008).…”

“…The JNK pathways include nuclear and non-nuclear pathways (Han et al, 2008). Activated JNK phosphorylates nuclear substrate, the transcription factor c-Jun, which leads to increase of activator protein-1 transcription activity to modulate transcription of genes related to apoptosis.…”