Differential sensitivity of the inner ear sensory cell populations to forced cell cycle re-entry and p53 induction.
Previous studies have shown that the maintenance of post-mitotic state is critical for the life-long survival of the inner ear mechanosensory cells, the hair cells. A general concept is that differentiated, post-mitotic cells rapidly die following cell cycle re-entry. Here we have compared the response of postnatal cochlear (auditory) and utricular (balance) hair cells to forced cell cycle reactivation and p53 up-regulation. Forced S-phase entry was triggered through the human papillomavirus-16 E7 oncogene misexpression in explant cultures. It induced DNA damage and p53 induction in cochlear outer hair cells and these cells were rapidly lost, before entry into mitosis. The death was attenuated by p53 inactivation. In contrast, despite DNA damage and p53 induction, utricular hair cells showed longer term survival and a proportion of them progressed into mitosis. Consistently, pharmacological elevation of p53 levels by nutlin-3a led to a death-prone phenotype of cochlear outer hair cells, while other hair cell populations were death-resistant. These data have important clinical implications as they show the importance of p53 in sensory cells that are essential in hearing function.
Sulg
Marilin
M
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Kirjavainen
Anna
A
Pajusola
Katri
K
Bueler
Hansruedi
H
Ylikoski
Jukka
J
Laiho
Marikki
M
Pirvola
Ulla
U
D000256:Adenoviridae / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D064026:Calbindins; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage / Q000502:physiology; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000378:metabolism; D007758:Ear, Inner / Q000166:cytology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D007093:Imidazoles / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000378:metabolism; D008465:Mechanoreceptors / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D064030:S100 Calcium Binding Protein G / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D056189:Viral Tropism / Q000235:genetics / Q000502:physiology
D064026:Calbindins; D007093:Imidazoles; D019394:Ki-67 Antigen; D010320:Parvalbumins; D010879:Piperazines; D064030:S100 Calcium Binding Protein G; D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins; C012244:5-chloro-2'-deoxyuridine; C482205:nutlin 3; D003857:Deoxyuridine