Differential sensitivity of the inner ear sensory cell populations to forced cell cycle re entry and p53 induction英文文献.pdfVIP

JOURNAL OF NEUROCHEMISTRY | 2010 | 112 | 1513–1526 doi: 10.1111/j.1471-4159.2009.06563.x ,1 *Institute of Biotechnology, University of Helsinki, Helsinki, Finland Molecular Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland College of Medicine, University of Kentucky, Lexington, Kentucky, USA Abstract death was attenuated by p53 inactivation. In contrast, despite Previous studies have shown that the maintenance of post- DNA damage and p53 induction, utricular hair cells showed mitotic state is critical for the life-long survival of the inner ear longer term survival and a proportion of them progressed into mechanosensory cells, the hair cells. A general concept is that mitosis. Consistently, pharmacological elevation of p53 levels differentiated, post-mitotic cells rapidly die following cell cycle by nutlin-3a led to a death-prone phenotype of cochlear outer re-entry. Here we have compared the response of postnatal hair cells, while other hair cell populations were death-resis- cochlear (auditory) and utricular (balance) hair cells to forced tant. These data have important clinical implications as they cell cycle reactivation and p53 up-regulation. Forced S-phase show the importance of p53 in sensory cells that are essential entry was triggered through the human papillomavirus-16 E7 in hearing function. oncogene misexpression in explant cultures. It induced DNA Keywords: cell cycle re-entry, cell death, DNA damage, damage and p53 induction in cochlear outer hair cells and inner ear hair cell, p53, nutlin-3a. these cells were rapidly lost, before entry into mitosis. The