TY - JOUR T1 - c-Jun N-Terminal Phosphorylation: Biomarker for Cellular Stress Rather than Cell Death in the Injured Cochlea JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0047-16.2016 VL - 3 IS - 2 SP - ENEURO.0047-16.2016 AU - Tommi Anttonen AU - Anni Herranen AU - Jussi Virkkala AU - Anna Kirjavainen AU - Pinja Elomaa AU - Maarja Laos AU - Xingqun Liang AU - Jukka Ylikoski AU - Axel Behrens AU - Ulla Pirvola Y1 - 2016/03/01 UR - http://www.eneuro.org/content/3/2/ENEURO.0047-16.2016.abstract N2 - Prevention of auditory hair cell death offers therapeutic potential to rescue hearing. Pharmacological blockade of JNK/c-Jun signaling attenuates injury-induced hair cell loss, but with unsolved mechanisms. We have characterized the c-Jun stress response in the mouse cochlea challenged with acoustic overstimulation and ototoxins, by studying the dynamics of c-Jun N-terminal phosphorylation. It occurred acutely in glial-like supporting cells, inner hair cells, and the cells of the cochlear ion trafficking route, and was rapidly downregulated after exposures. Notably, death-prone outer hair cells lacked c-Jun phosphorylation. As phosphorylation was triggered also by nontraumatic noise levels and none of the cells showing this activation were lost, c-Jun phosphorylation is a biomarker for cochlear stress rather than an indicator of a death-prone fate of hair cells. Preconditioning with a mild noise exposure before a stronger traumatizing noise exposure attenuated the cochlear c-Jun stress response, suggesting that the known protective effect of sound preconditioning on hearing is linked to suppression of c-Jun activation. Finally, mice with mutations in the c-Jun N-terminal phosphoacceptor sites showed partial, but significant, hair cell protection. These data identify the c-Jun stress response as a paracrine mechanism that mediates outer hair cell death. ER -