NF-kappaB-dependent apoptotic hair cell death in the auditory system.
Hair cells are the most vulnerable elements in the inner ear and their degeneration is the most common cause of hearing loss. In the last few years progress has been made in uncovering the molecular mechanisms involved in hair cell damage and death. However, little is known about factors important for hair cell survival. Recently, it has been demonstrated that the transcription factor NF-kappaB is required for survival of immature auditory hair cells in vitro. Here we used DNA microarray technology to explore NF-kappaB downstream events in organ of Corti explants of postnatal day-5 Sprague-Dawley rats which were exposed to a cell-permeable NF-kappaB-inhibitory peptide. Gene expression was analyzed using DNA microarray technology. Genes were selected on the basis of comparative analysis, which reliably distinguished the NF-kappaB inhibitor-treated samples from control samples. Interestingly, among the up-regulated genes was the gene coding for the regulatory subunit of phosphatidylinositol 3-kinase. Moreover, inhibition of the phosphatidylinositol 3-kinase signaling pathway in organ of Corti explants exposed to the NF-kappaB inhibitor reduced caspase-3 activation. These data link NF-kappaB-dependent hair cell death to phosphatidylinositol 3-kinase signaling.
Nagy
Ivana
I
Inner Ear Research, Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Zurich, NORD 2, and Center for Integrative Human Physiology (ZIHP), Zurich, Switzerland.
Caelers
Antje
A
Monge
Arianne
A
Bonabi
Sharouz
S
Huber
Alexander M
AM
Bodmer
Daniel
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D006198:Hair Cells, Auditory / Q000166:cytology* / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D010455:Peptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
D053148:Caspase 3; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D016328:NF-kappa B; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one