title: p27(Kip1) is required to maintain proliferative quiescence in the adult cochlea and pituitary.
abstract: Cell cycle inhibitors, such as the cyclin-dependent kinase (Cdk) inhibitor proteins and retinoblastoma (Rb) family members, control exit from the cell cycle during the development of a variety of terminally differentiated tissues. It is unclear whether sustained expression of these proteins is required to prevent cell cycle re-entry in quiescent and terminally differentiated cells. The organ of Corti (cochlear sensory epithelium) and pars intermedia (intermediate lobe of the pituitary) are two tissues that share the characteristic of ongoing cell division in mice lacking either the p27(Kip1) Cdk inhibitor, Ink4 proteins, or Rb. Here, we use tamoxifen-inducible mouse models to delete p27(Kip1) in postnatal animals and show this is sufficient to induce proliferation in both the organ of Corti and pars intermedia. Thus, these tissues remain sensitive to the presence of p27(Kip1) even after their developmental exit from the cell cycle. The neonatal cochlea displayed heightened sensitivity to changes in p27(Kip1) expression, with a proliferative response higher than that of constitutive null mice. In adults, the proliferative response was reduced but was accompanied by increased cell survival. In contrast, re-establishment of normal p27(Kip1) expression in animals with established pituitary tumors, in an inducible "knock-on" model, led to cessation of pituitary tumor growth, indicating the cells had maintained their susceptibility to p27-mediated growth suppression. Although restoration of p27(Kip1) did not induce apoptosis, it did lead to resolution of pathological features and normalization of gene expression. Our data underscore the importance of p27(Kip1) expression in the maintenance of cellular quiescence and terminal differentiation.
authors.affiliation: Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, WA, USA. oesterle@uw.edu
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Oesterle
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Chien
authors.forename: Sean
authors.initials: S
authors.lastname: Campbell
authors.forename: Praveena
authors.initials: P
authors.lastname: Nellimarla
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Fero
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival; D002645:Chickens; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D009925:Organ of Corti / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D038081:Organogenesis; D052716:Pituitary Gland, Intermediate / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; D016213:Cyclins; D016160:Retinoblastoma Protein; D013629:Tamoxifen; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases