Role of differential phosphorylation of c-Jun N-terminal domain in degenerative and regenerative actions of c-jun in the nervous system

• Applicant: Professorin Dr. Anna Maria Musti
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2008 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 77820947

c-Jun is a major component of the transcription factor AP-1, a paradigm for transcriptional response to extracellular signals. c-Jun transactivity is mainly regulated by the SAPK-JNK pathway through phosphorylation of its N-terminal domain. Depending on the type of stimulus and genetic background, JNK-mediated activation of c-Jun can elicit quite diverse programs, as cell cycle progression, or differentiation and apoptosis of several cell types. A bipartite function of c-Jun is also evident within the central nervous system, were its ablation impairs regeneration of injured peripheral nerve fibers, but it also reduces cell death. We have recently demonstrated that abrogation of c-Jun phosphorylation at the ATM/ATR consensus site T95 impairs stress-induced biological activity of c-Jun, as transactivity and enhancement of cell death. Moreover, our preliminary experiments in PC12 cells indicate that abrogation of T95 phosphorylation does not impair the ability of c-Jun to induce neurite outgrowth in naïve cells, while it inhibits c-Jun proapoptotic phosphorylation at the T91/T93 JNK sites in NGF-differentiated cells. These observations suggest that lack of T95 phosphorylation may protect postmitotic neurons from stress-induced apoptosis without interfering with neuronal differentiation. The ultimate goal of our project is to assess whether the selective inhibition of c-Jun phosphorylation at T95 may represent a pharmacological tool to selectively target degenerative pathways in the nervous system. To this purpose, we will investigate the physiological relevance of c-Jun phosphorylation at T95 in degenerative and regenerative processes of the nervous system, by generating a mouse model were the endogenous c-Jun gene is replaced by a mutant c-Jun allele carrying alanine substitution of T95. Furthermore, by generating a phospho-antibody specific for T95-phosphorylated c-Jun, we will identify the signaling pathway(s) regulating T95 phosphorylation in neuronal cells.

• DFG Programme: Research Grants