p53 Deficiency Leads to Compensatory Up-Regulation of p16INK4a

Leong, Wai Fook; Chau, Jenny Fung Ling; Li, Baojie

doi:10.1158/1541-7786.mcr-08-0373

Cited by 54 publications

(54 citation statements)

References 17 publications

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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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“…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%

“…On the contrary, BCPAP, a cell line which harbors a mutant copy of p53, did not show any changes in the parameters measured at the low dose of irradiation. Evidence of cross-talk between the p53-p21 and p16-pRb pathways has existed for some time (34,35). However, the exact nature of this cross-talk is not entirely clear.…”

Section: Discussionmentioning

confidence: 99%

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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“…In addition, CKB, the brain creatine kinase gene (Zhao et al, 1994) and ID1, an inhibitor of differentiation/DNA binding (Qian and Chen, 2008) are p53-dependent down-regulated genes, EFEMP2, EGFcontaining fibulin-like extracellular matrix protein 2, and mutant p53-binding protein 1 (MBP1) (Gallagher et al, 1999) expression levels are decreased after exposure to space radiations and in the space environment (Tables S4 and S6). Although H19, known as insulin-like growth factor II (Igf2) (Dugimont et al, 1998) and CDKN2A, known as p16/INK4a (Leong et al, 2009) were p53-downregulated genes, the expression of these genes was increased in a p53-dependent manner in these space experiments (Tables S1-S3). In addition, although Noxa, noxious stress inducible pro-apoptotic gene (Oda et al, 2000a); CDH1, cadherin 1 known as E-cadherin (Bukholm et al, 1997); HMOX1, heme oxygenase 1 known as HO-1 (Meiller et al, 2007); CKM, muscle creatine kinase gene (Zhao et al, 1994); Gadd45, growth arrest and DNA-damage-inducible gene 45 (Kastan et al, 1992); SMAD7, Sma-and Mad-related protein family member 7 (Zhang et al, 2006) and BNIP3L, BCL2/adenovirus E1B 19kDa interacting protein 3-like (Fei et al, 2004) were reported to be p53-dependent up-regulated genes, whereas these genes were depressed in a p53 dependent manner in these space experiments (Tables S4 and S6).…”

Section: The Expression Of P53-dependent Regulated Genes In the Cultumentioning

confidence: 91%

The First Life Science Experiments in ISS: Reports of "Rad Gene"-Space Radiation Effects on Human Cultured Cells-

Takahashi

Nagamatsu

et al. 2010

Biol. Sci. Space

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To clarif y the biological ef fe cts of space environment, especially space radiations, a proposal of " Rad Gene" was performed as the first life science experiment with two human lymphoblastoid cell lines bearing wild-type p53 gene (wtp53) and mutated p53 gene (mp53) in an International Space Station (ISS) for 133 days. We scheduled four projects: (1) DNA damage induced by space radiations including the high linear energy transfer (LET) particles was detected as a track of γH2AX foci in the nuclei of these frozen cells. (2) To examine the biological effects of microgravity and space radiations on gene and protein expression of p53 -dependent regulated genes, these cells were grown under microgravity and 1 gravity in ISS, and on ground for 8 days and analyzed by DNA and protein arrays. (3) p53-Dependent regulated genes were analyzed in the cultured cells after spaceflight at frozen state exposed to space radiations. (4) To clarify the effects of space radiations on the radioadaptive response, the space flown cells at frozen state were cultured, and then exposed to challenging X-ray-irradiation. All of the radioadaptive responses of cell killing, apoptosis, chromosomal aberrations and mutations were found only in wtp53 cells, but not in the mp53 cells.

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p53 Deficiency Leads to Compensatory Up-Regulation of p16INK4a

Cited by 54 publications

References 17 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

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

The First Life Science Experiments in ISS: Reports of "Rad Gene"-Space Radiation Effects on Human Cultured Cells-

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