Differential sensitivity of the inner ear sensory cell populations to forced cell cycle re-entry and p53 induction

Marilin Sulg, Anna Kirjavainen, Katri Pajusola, Hansruedi Bueler, Jukka Ylikoski, Marikki Laiho, Ulla Pirvola

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1513-1526
Number of pages14
JournalJournal of Neurochemistry
Volume112
Issue number6
DOIs
StatePublished - Mar 2010
Externally publishedYes

Fingerprint

Reentry
Inner Ear
Cell Cycle
Cells
Outer Auditory Hair Cells
Population
Mitosis
DNA Damage
Human papillomavirus 16
DNA
Cochlea
Audition
S Phase
Oncogenes
Hearing
Up-Regulation
Maintenance
Pharmacology
Phenotype

Keywords

  • Cell cycle re-entry
  • Cell death
  • DNA damage
  • Inner ear hair cell
  • Nutlin-3a
  • P53

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Differential sensitivity of the inner ear sensory cell populations to forced cell cycle re-entry and p53 induction. / Sulg, Marilin; Kirjavainen, Anna; Pajusola, Katri; Bueler, Hansruedi; Ylikoski, Jukka; Laiho, Marikki; Pirvola, Ulla.

In: Journal of Neurochemistry, Vol. 112, No. 6, 03.2010, p. 1513-1526.

Research output: Contribution to journalArticle

Sulg, Marilin ; Kirjavainen, Anna ; Pajusola, Katri ; Bueler, Hansruedi ; Ylikoski, Jukka ; Laiho, Marikki ; Pirvola, Ulla. / Differential sensitivity of the inner ear sensory cell populations to forced cell cycle re-entry and p53 induction. In: Journal of Neurochemistry. 2010 ; Vol. 112, No. 6. pp. 1513-1526.
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