c-Jun expression, activation and function in neural cell death, inflammation and repair

Up-regulation of c-Jun is a common event in the developing, adult as well as in injured nervous system that serves as a model of transcriptional control of brain function. Functional studies employing in vivo strategies using gene deletion, targeted expression of dominant negative isoforms and pharmacological inhibitors all suggest a three pronged role of c-Jun action, exercising control over neural cell death and degeneration, in gliosis and inflammation as well as in plasticity and repair. In vitro, structural and molecular studies reveal several non-overlapping activation cascades via N-terminal c-Jun phosphorylation at serine 63 and 73 (Ser63, Ser73), and threonine 91 and 93 (Thr91, Thr93) residues, the dephosphorylation at Thr239, the p300-mediated lysine acetylation of the near C-terminal region (Lys268, Lys271, Lys 273), as well as the Jun-independent activities of the Jun N-terminal family of serine/threonine kinases, that regulate the different and disparate cellular responses. A better understanding of these non-overlapping roles in vivo could considerably increase the potential of pharmacological agents to improve neurological outcome following trauma, neonatal encephalopathy and stroke, as well as in neurodegenerative disease.