p19^Ink4dand p21^Cip1Collaborate to Maintain the Postmitotic State of Auditory Hair Cells, Their Codeletion Leading to DNA Damage and p53-Mediated Apoptosis

Abstract

Sensory hair cells of the auditory organ are generated during embryogenesis and remain postmitotic throughout life. Previous work has shown that inactivation of the cyclin-dependent kinase inhibitor (CKI) p19Ink4d leads to progressive hearing loss attributable to inappropriate DNA replication and subsequent apoptosis of hair cells. Here we show the synergistic action of another CKI, p21 Cip1 , on cell cycle reactivation. The codeletion of p19Ink4d and p21 Cip1 triggered profuse S-phase entry of auditory hair cells during a restricted period in early postnatal life, leading to the transient appearance of supernumerary hair cells. In addition, we show that aberrant cell cycle reentry leads to activation of a DNA damage response pathway in these cells, followed by p53-mediated apoptosis. The majority of hair cells were absent in adult cochleas. These data, together with the demonstration of changing expression patterns of multiple CKIs in auditory hair cells during the stages of early postnatal maturation, show that the maintenance of the postmitotic state is an active, tissue-specific process, cooperatively regulated by several CKIs, and is critical for the lifelong survival of these sensory cells.

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

“…31 Moreover, abnormal DNA replication leading to p53-dependent apoptosis and inner ear involution occurs after concomitant inactivation of p19 ARF and p21 CIP1 CDKis. 32 In line with these studies, our data showing that in vivo inhibition of DNA replication dose dependently prevents activation of the DDR and accumulation of p53 provide support for the notion that replication stress has a major causative role in p53 activation in cells lacking E2F1 and E2F2.…”

A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells

“…ENU Mutagenesis, Functional Studies, Positional Cloning, Histology, and Biochemistry. ENU mutagenesis, analysis of ABRs and distortion product otoacoustic emissions, test of vestibular function, staining of sections and whole mounts, electron microscopy, positional cloning, the expression and purification of recombinant CDH23 and PCDH15, and protein interaction studies have been described previously (16,35,47,48). Tip tenting was quantified by counting tented stereocilia in the medium row in inner hair cell bundles (in 2-6 hair cells per time point and genotype).…”

Genetic disruption of the Nrf2 compromises cell-cycle progression by impairing GSH-induced redox signaling

“…An Nrf2 deficiency is associated with enhanced expression levels of genes involved in cell-cycle checkpoints' regulation, including the cyclin-dependent kinase inhibitor 2D (Cdkn2d, p19) and promyelocytic leukemia (PML). Cdkn2d inhibits Cdk4 leading to cell-cycle arrest at the G 1 /S transition (Buchold et al, 2007;Laine et al, 2007), whereas PML recruits Chk family kinases and p53 into the PML nuclear bodies, enhances the p53/Chk2 interaction (Louria-Hayon et al, 2003) and also orchestrates a nuclear tumor suppressor network that inactivate nuclear pAkt (Trotman et al, 2006). Cenp-F and Cenp-E have been implicated in spindle checkpoint regulation, kinetochore-microtubule capture and chromosome alignment and stability (Parra et al, 2002;Putkey et al, 2002).…”