Requirement of JNK for Stress- Induced Activation of the Cytochrome c-Mediated Death Pathway

Abstract

The c-Jun NH2-terminal kinase (JNK) is activated when cells are exposed to ultraviolet (UV) radiation. However, the functional consequence of JNK activation in UV-irradiated cells has not been established. It is shown here that JNK is required for UV-induced apoptosis in primary murine embryonic fibroblasts. Fibroblasts with simultaneous targeted disruptions of all the functional Jnk genes were protected against UV-stimulated apoptosis. The absence of JNK caused a defect in the mitochondrial death signaling pathway, including the failure to release cytochrome c. These data indicate that mitochondria are influenced by proapoptotic signal transduction through the JNK pathway.

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

“…Further support arose from data obtained using dominant-negative c-Jun mutants, which reduced sympathetic neuronal death following NGF withdrawal [214]. A pro-apoptotic function has also been suggested for JNK activation in NGFwithdrawal-induced neuronal death [59] in a hippocampal model of Huntington's disease [124] and in beta-amyloidinduced neuronal apoptosis [204]. However, the apoptotic process does not occur in JNK-knockout mice [222] or mice expressing a mutant form of c-Jun lacking the JNK phosphorylation site [15].…”

“…This malfunction is significant since it is critical for the subsequent sequential activation of Apaf-1 [120], the initiator-caspase caspase-9 [76] and finally the effector-caspase caspase-3 [217] all of which are essential in the execution of apoptosis. Tournier et al [204] suggested that the apoptotic response is suppressed in JNK null MEF due to the absence of JNK, which is needed to initiate the apoptotic cascade (Fig. 5).…”

“…This hypothesis is based on observations in primary murine embryonic fibroblasts (MEF) lacking the genes for JNK1 and JNK2 (JNK null; no JNK1/2 protein/activity). These JNK null MEF exhibit profound defects in stress-induced (UV-radiation, DNA-alkylation, translational inhibition) apoptosis [204]. The defect in the execution of apoptotic cell death was caused by the failure to initiate JNK-induced cytochrome c release from the mitochondria [204].…”

“…These JNK null MEF exhibit profound defects in stress-induced (UV-radiation, DNA-alkylation, translational inhibition) apoptosis [204]. The defect in the execution of apoptotic cell death was caused by the failure to initiate JNK-induced cytochrome c release from the mitochondria [204]. This malfunction is significant since it is critical for the subsequent sequential activation of Apaf-1 [120], the initiator-caspase caspase-9 [76] and finally the effector-caspase caspase-3 [217] all of which are essential in the execution of apoptosis.…”

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

“…38 We have previously shown that agonist RRMs induce a strong and sustained activation of stress kinases JNK and p38, which correlates with the induction of apoptosis. 39 JNK is necessary for the release of cytochrome c during stressinduced apoptosis 40 and is known to phosphorylate Bcl-2 and Bcl-X L , hindering their antiapoptotic function. [41][42][43] This contrasts with other studies suggesting that Bcl-2 phosphorylation is required for its antiapoptotic activity.…”