PT  - JOURNAL ARTICLE
AU  - Anttonen, Tommi
AU  - Herranen, Anni
AU  - Virkkala, Jussi
AU  - Kirjavainen, Anna
AU  - Elomaa, Pinja
AU  - Laos, Maarja
AU  - Liang, Xingqun
AU  - Ylikoski, Jukka
AU  - Behrens, Axel
AU  - Pirvola, Ulla
TI  - c-Jun N-Terminal Phosphorylation: Biomarker for Cellular Stress Rather than Cell Death in the Injured Cochlea
AID  - 10.1523/ENEURO.0047-16.2016
DP  - 2016 Mar 01
TA  - eneuro
PG  - ENEURO.0047-16.2016
VI  - 3
IP  - 2
4099  - http://www.eneuro.org/content/3/2/ENEURO.0047-16.2016.short
4100  - http://www.eneuro.org/content/3/2/ENEURO.0047-16.2016.full
SO  - eneuro2016 Mar 01; 3
AB  - 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.