Real-time in vivo imaging of p16<sup>Ink4a</sup>reveals cross talk with p53

Yamakoshi, Kimi; Takahashi, Akiko; Hirota, Fumiko; Nakayama, Ryu; Ishimaru, Naozumi; Kubo, Yoshiaki; Mann, David J.; Ohmura, Masako; Hirao, Atsushi; Saya, Hideyuki; Arase, Seiji; Hayashi, Yoshio; Nakao, Kazuki; Matsumoto, Machiko; Ohtani, Naoko; Hara, Eiji

doi:10.1084/jem2069oia18

Cited by 6 publications

(6 citation statements)

References 54 publications

(79 reference statements)

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“…The molecular circuitry mediating this loop, and the potential role played in it by known regulators of the Ink4a locus, such as Polycomb, p63 and E2F proteins (5), require further analysis. Our finding that p53 mediates this positive loop stands in contrast to previous studies reporting suppression of p16 Ink4 /p19 ARF by p53 (38)(39)(40). Compensatory activation of these genes in situations of p53 loss may occur through a distinct pathway.…”

Section: Discussioncontrasting

confidence: 99%

Dynamics of Senescent Cell Formation and Retention Revealed by p14ARF Induction in the Epidermis

et al. 2013

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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 p14 ARF (human ortholog of murine p19 ARF ), a central activator of senescence. Induction of p14 ARF 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 p16 Ink4a were activated by the transgenic p14 ARF through p53, revealing a senescence-promoting feed-forward loop. Commitment of cells to senescence required continued p14 ARF 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 p14 ARF induction, but irreversibly lost their ability to proliferate and initiate follicle growth.Interestingly, induction of epidermal hyperplasia prevented the appearance of senescent cells upon p14 ARF 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. Ó2013 AACR.

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Section: Discussioncontrasting

confidence: 99%

Dynamics of Senescent Cell Formation and Retention Revealed by p14ARF Induction in the Epidermis

et al. 2013

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“…p16 expression was restored by treatment with the DNA hypomethylating agent 5-aza-2′-deoxycytidine (DAC) (Supplemental Figure 5A), providing further validation that p16 silencing is not due to unforeseen side effects of the cis element knockin. Importantly, consistent with previous studies (28,29), we observed concomitant increases in repressive histone markers (H3K9me2 and H3K27me3), with no changes of active markers (H3K9Ac and H3K4me3), across the p16 promoter (Supplemental Figure 5B), which suggests that cis-mediated epigenetic silencing could be mechanistically reinforced by changes in chromatin configuration.…”

Section: Resultssupporting

confidence: 92%

Targeted p16Ink4a epimutation causes tumorigenesis and reduces survival in mice

Yu¹,

Waterland²,

Zhang³

et al. 2014

J. Clin. Invest.

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“…However, the exact nature of this cross-talk is not entirely clear. It has now emerged that p53 may inhibit p16 levels and that in the absence of wild-type p53, p16 levels increase as a back-up mechanism (35,36). Our results suggest that the p16 response to radiation is dependent on the p53 status of the cells where the former was up-regulated in response to radiation in the TPC-1 cell line with wild-type p53.…”

Section: Discussionmentioning

confidence: 64%

Response to low-dose X-irradiation is p53-dependent in a papillary thyroid carcinoma model system

et al. 2011

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Abstract. The link between high doses of radiation and thyroid cancer has been well established in various studies, as opposed to the effects of low doses. In this study, we investigated the effects of low-dose X-ray irradiation in a papillary thyroid carcinoma model with wild-type and mutated p53. A low dose of 62.5 mGy was enough to cause an upregulation of p16 and a decrease in the number of TPC-1 cells in the S phase, but not in the number of BCPAP p53-mutant cells. At a dose of 0.5 Gy, visible signs of senescence appeared only in the TPC-1 cells. We conclude that low doses of X-rays are enough to cause a change in cell cycle distribution, possibly p53-dependent p16 activation, but no significant apoptosis. Senescence requires higher doses of X-irradiation via a mechanism involving both p16 and p21.

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Real-time in vivo imaging of p16^Ink4areveals cross talk with p53

Cited by 6 publications

References 54 publications

Dynamics of Senescent Cell Formation and Retention Revealed by p14ARF Induction in the Epidermis

Dynamics of Senescent Cell Formation and Retention Revealed by p14ARF Induction in the Epidermis

Targeted p16Ink4a epimutation causes tumorigenesis and reduces survival in mice

Response to low-dose X-irradiation is p53-dependent in a papillary thyroid carcinoma model system

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Real-time in vivo imaging of p16Ink4areveals cross talk with p53

Cited by 6 publications

References 54 publications

Dynamics of Senescent Cell Formation and Retention Revealed by p14ARF Induction in the Epidermis

Dynamics of Senescent Cell Formation and Retention Revealed by p14ARF Induction in the Epidermis

Targeted p16Ink4a epimutation causes tumorigenesis and reduces survival in mice

Response to low-dose X-irradiation is p53-dependent in a papillary thyroid carcinoma model system

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Real-time in vivo imaging of p16^Ink4areveals cross talk with p53