title: c-Jun N-Terminal Phosphorylation: Biomarker for Cellular Stress Rather than Cell Death in the Injured Cochlea.
abstract: 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.
authors.affiliation: Department of Biosciences, University of Helsinki , 00014 Helsinki, Finland.
authors.forename: Tommi
authors.initials: T
authors.lastname: Anttonen
authors.affiliation: Department of Biosciences, University of Helsinki , 00014 Helsinki, Finland.
authors.forename: Anni
authors.initials: A
authors.lastname: Herranen
authors.affiliation: Finnish Institute of Occupational Health , 00251 Helsinki, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Virkkala
authors.affiliation: Department of Biosciences, University of Helsinki , 00014 Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kirjavainen
authors.affiliation: Department of Biosciences, University of Helsinki , 00014 Helsinki, Finland.
authors.forename: Pinja
authors.initials: P
authors.lastname: Elomaa
authors.affiliation: Department of Biosciences, University of Helsinki , 00014 Helsinki, Finland.
authors.forename: Maarja
authors.initials: M
authors.lastname: Laos
authors.affiliation: Department of Biosciences, University of Helsinki , 00014 Helsinki, Finland.
authors.forename: Xingqun
authors.initials: X
authors.lastname: Liang
authors.affiliation: Helsinki Ear Institute , 00420 Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Ylikoski
authors.affiliation: The Francis Crick Institute and King's College London , London SE1 1UL, UK.
authors.forename: Axel
authors.initials: A
authors.lastname: Behrens
authors.affiliation: Department of Biosciences, University of Helsinki , 00014 Helsinki, Finland.
authors.forename: Ulla
authors.identifier: 0000-0001-5285-4225
authors.initials: U
authors.lastname: Pirvola
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018069:Hair Cells, Vestibular / Q000378:metabolism*; D006317:Hearing Loss, Noise-Induced / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007612:Kanamycin / Q000633:toxicity; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009622:Noise / Q000009:adverse effects; D011500:Protein Synthesis Inhibitors / Q000633:toxicity; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D061285:Vestibulocochlear Nerve Injuries / Q000139:chemically induced / Q000473:pathology*
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; D011500:Protein Synthesis Inhibitors; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D007612:Kanamycin; D048031:JNK Mitogen-Activated Protein Kinases
keywords: c-Jun phosphorylation; cell death; hair cell; inner ear; noise; supporting cell