C-Jun and the c-Jun amino-terminal kinases: Bipotential components of the neuronal stress response

Expression of the inducible transcription factor c-Jun in neurons is a common finding after neuronal injury or 'stress,' such as ischemia, excitotoxicity, axon transection, UV irradiation, stimulation by cytokines, or production of such lipid messengers as ceramide. The neuronal 'stress response' displays striking similarities to the stress response of other cell types such as lymphocytes or tumor cells and is characterized by the activation of programs that lead to apoptosis or survival. It is accepted knowledge that c-Jun can act as neuronal 'killer' under in vitro conditions (with the death inducing ligand fas-ligand as novel AP-1 controlled target gene), but there is also growing evidence that c-Jun is linked to neuronal repair or survival. The control of this dichotomous function of c-Jun is not fully understood. Similar to the expression of c-Jun, the transcriptional activation of c-Jun by amino-terminal phosphorylation and the activation of the catalyzing c-Jun amino-terminal kinases (JNK), also called stress activated protein kinases, can also be linked to both neuronal survival and apoptosis. We suggest a model for the control of gene transcription after neuronal stress with activation of JNK and phosphorylation of c-Jun as transcriptional prerequisites, and with associated partners as transcriptional effecters, e,g,, by the expression and/or suppression of other transcription factors as activating transcription factor 2 (ATF-2), c-Fos, or JunD. This scenario is complicated by the observation that activity of JNK does not lead automatically to c-Jun phosphorylation. This review summarizes the role of c-Jun and JNK as down-stream mediators of neuronal stressors and places the function of these molecules in the context of other stressful stimuli and intraneuronal responses.