Alteration of activator protein 1 DNA binding activity in gentamicin-induced hair cell degeneration

Neuroscience. 2006 Feb;137(3):971-80. doi: 10.1016/j.neuroscience.2005.10.010. Epub 2005 Dec 7.


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.

MeSH terms

  • Actins / biosynthesis
  • Actins / genetics
  • Animals
  • Binding, Competitive / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • DNA / metabolism*
  • Electrophoretic Mobility Shift Assay
  • Genes, fos / genetics
  • Gentamicins / toxicity*
  • Hair Cells, Auditory / drug effects
  • Hair Cells, Auditory / metabolism
  • Hair Cells, Auditory / pathology*
  • Immunohistochemistry
  • MAP Kinase Kinase 4 / physiology
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology*
  • Organ Culture Techniques
  • Protein Binding
  • Protein Synthesis Inhibitors / toxicity*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / physiology
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*


  • Actins
  • Gentamicins
  • Protein Synthesis Inhibitors
  • Transcription Factor AP-1
  • DNA
  • MAP Kinase Kinase 4