Alteration of activator protein 1 DNA binding activity in gentamicin-induced hair cell degeneration.
Sensorineural hearing loss is often associated with damage of cochlear hair cells and/or of the neurons of the auditory pathway. This damage can result from a variety of causes, e.g. genetic disorders, aging, exposure to certain drugs such as aminoglycosides, infectious disease and intense sound overexposure. Intracellular events that mediate aspects of aminoglycoside-mediated damage to hair cells have been partially unraveled. Several independent research groups have demonstrated a crucial role of mitogen-activated protein kinase signaling in aminoglycoside-induced ototoxicity. Mitogen-activated protein kinases are important mediators of signal transduction from the cell surface to the nucleus. Jun N-terminal kinases, members of the mitogen-activated protein kinase family, are strongly activated in cell culture conditions by stress inducing stimuli, including ultraviolet light, heat shock and tumor necrosis factor; therefore they are also referred to as stress-activated protein kinases. In hair cells aminoglycoside treatment was shown to activate the Jun N-terminal kinase signaling pathway. Activation of Jun N-terminal kinase leads to phosphorylation and thereby activation of transcription factors and consequently to altered gene expression. There are many nuclear Jun N-terminal kinase substrates including c-Jun, ATF-2, and Elk-1 proteins. One of the downstream targets of Jun N-terminal kinase is the transcription factor activating protein-1. Activating protein-1 is a dimeric complex composed of members of the Fos and Jun proteins. A variety of different stimuli is known to induce activating protein-1 activity. Induction of activating protein-1 is thought to play a central role in reprogramming gene expression in response to external stimuli. In this study we have analyzed the effect of gentamicin treatment on the downstream targets of Jun N-terminal kinase. Our results demonstrate that gentamicin treatment of explants of organ of Corti results in increased activating protein-1 binding activity. The main component of these activating protein-1 complexes is the c-Fos protein. Moreover, we show that the activating protein-1 induction is transient and occurs exclusively in hair cells of rat organ of Corti explants.
Albinger-Hegyi
A
A
Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University Hospital Zürich, Frauenklinikstr. 24, 8091 Zurich, Switzerland.
Hegyi
I
I
Nagy
I
I
Bodmer
M
M
Schmid
S
S
Bodmer
D
D
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D016762:Genes, fos / Q000235:genetics; D005839:Gentamicins / Q000633:toxicity*; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D048670:MAP Kinase Kinase 4 / Q000502:physiology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D009924:Organ Culture Techniques; D011485:Protein Binding; D011500:Protein Synthesis Inhibitors / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D005839:Gentamicins; D011500:Protein Synthesis Inhibitors; D018808:Transcription Factor AP-1; D004247:DNA; D048670:MAP Kinase Kinase 4