Dynamics of senescent cell formation and retention revealed by p14 ARF induction in the epidermis

Ronit Tokarsky-Amiel, Narmen Azazmeh, Aharon Helman, Yan Stein, Alia Hassan, Alexander Maly, Ittai Ben-Porath*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Cellular senescence, a state of cell-cycle arrest accompanied by dramatic morphologic and metabolic changes, is a central means by which cells respond to physiologic stress and oncogene activity. Senescence is thought to play important roles in aging and in tumor suppression, yet the dynamics by which senescent cells are formed, their effects on tissue function and their eventual fate are poorly understood. To study cellular senescence within an adult tissue, we developed transgenic mice inducibly expressing p14ARF (human ortholog of murine p19ARF), a central activator of senescence. Induction of p14ARF in the epidermis rapidly led to widespread apoptosis and cellcycle arrest, a stage that was transient, and was followed by p53-dependent cellular senescence. The endogenous Cdkn2a products p19 ARF and p16Ink4a were activated by the transgenic p14 ARF through p53, revealing a senescence-promoting feed-forward loop. Commitment of cells to senescence required continued p14ARF expression, indicating that entry into this state depends on a persistent signal. However, once formed, senescent cells were retained in the epidermis, often for weeks after transgene silencing, indicating an absence of an efficient rapidly acting mechanism for their removal. Stem cells in the hair follicle bulge were largely protected from apoptosis upon p14ARF induction, but irreversibly lost their ability to proliferate and initiate follicle growth. Interestingly, induction of epidermal hyperplasia prevented the appearance of senescent cells upon p14ARF induction. Our findings provide basic insights into the dynamics of cellular senescence, a central tumorsuppressive mechanism, and reveal the potential for prolonged retention of senescent cells within tissues. Cancer Res; 73(9); 2829-39.

Original languageAmerican English
Pages (from-to)2829-2839
Number of pages11
JournalCancer Research
Issue number9
StatePublished - 1 May 2013


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