c-Jun N-Terminal Protein Kinase (JNK) 2/3 Is Specifically Activated by Stress, Mediating c-Jun Activation, in the Presence of Constitutive JNK1 Activity in Cerebellar Neurons

Abstract

c-Jun is considered a major regulator of both neuronal death and regeneration. Stress in primary cultured CNS neurons induces phosphorylation of c-Jun serines 63 and 73 and increased c-Jun protein. However, total c-Jun N-terminal protein kinase (JNK) activity does not increase, and no satisfactory explanation for this paradox has been available. Here we demonstrate that neuronal stress induces strong activation of JNK2/3 in the presence of constitutively and highly active JNK1. Correspondingly, neurons from JNK1(-/-) mice show lower constitutive activity and considerably higher responsiveness to stress. p38 activity can be completely inhibited without effect on c-Jun phosphorylation, whereas 10 micrometer SB203580 strongly inhibits neuronal JNK2/3, stress-induced c-Jun phosphorylation, induced c-Jun activity, and neuronal death in response to trophic withdrawal stress. Neither constitutive JNK1 activity nor total neuronal JNK activity were significantly affected by this concentration of drug. Thus, neuronal stress selectively activates JNK2/3 in the presence of mechanisms maintaining constitutive JNK1 activity, and this JNK2/3 activity selectively targets c-Jun, which is isolated from constitutive JNK1 activity.

The c‐Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK‐ERK and Akt‐independent mechanism

“…The ability of an independent pharmacological c-Raf inhibitor to promote neuronal survival suggests that the neuroprotective effect of GW5074 is either directly or indirectly due to its action on c-Raf. Another agent that is protective against LK-induced apoptosis is SB203580 (Yamagishi et al 2001;Coffey et al 2002), best known for its inhibition of p38 MAP kinase signaling. It has recently been discovered that SB203580 also inhibits c-Raf potently when assayed in vitro (Hall-Jackson et al 1999b) raising the possibility that its ability to inhibit c-Raf may contribute to its ability to protect against apoptosis in granule neurons and other neuronal types.…”

“…A number of reports have implicated JNKs in the promotion of neuronal apoptosis both in vivo and in cell culture systems (Coffey et al 2002). Although all three JNK proteins are expressed in neurons, the phosphorylation of c-jun is believed to be mediated by JNK2 or JNK3 (Bruckner et al 2001;Bruckner and Estus 2002;Coffey et al 2002).…”

C-jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis

“…JNK activation and nuclear translocation in neurons have been reported in vivo under different pathological conditions. Nuclear localization of JNK has been detected in degenerating neurons of Alzheimer patients (Zhu et al, 2001) and in cerebellar granule neurons (Coffey et al, 2000(Coffey et al, , 2002. JNK1 and JNK3 translocation from the cytosol to the nucleus in neurons can also be observed in experimental models of hypoxia (Zhang et al, 1998) and ischemia (Mizukami et al, 1997) respectively.…”

JNK regulates FoxO-dependent autophagy in neurons

“…However, JNK is regulated very differently in neurons. JNK1 remains constitutively activated under basal conditions, while JNK2 and JNK3 exhibit low basal activity and are stress-responsive (Coffey et al 2000(Coffey et al , 2002. The proautophagy role of JNK in nonneuronal cells has been reported to be mediated by JNK1 (Wei et al 2008).…”