p16INK4a reporter mice reveal age-promoting effects of environmental toxicants

Sorrentino, Jessica A.; Krishnamurthy, Janakiraman; Tilley, Stephen L.; Alb, James G.; Burd, Christin E.; Sharpless, Norman E.

doi:10.1172/jci70960

Cited by 70 publications

(70 citation statements)

References 34 publications

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“…The murine strain harbors a knock-in of the luciferase gene into the cdkn2a locus [34]. The model exposed to arsenic, cigarette smoke and UV light potently activated p16INK4a-mediated senescence [32].This in vivo data seems to corroborate our main conclusions. However, senescence is not the only physiological end point observed during environmental carcinogens stimuli.…”

Section: Discussionsupporting

confidence: 84%

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Cellular Senescence Controlled by p53 is a Barrier to Environmental Carcinogenesis

Carnero¹

2015

J Carcinog Mutagen

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Cancer development in humans and animals may be caused by environmental factors. It has been estimated that approximately 80% of human tumors are generated by exposure to environmental carcinogens. The carcinogens may initiate or induce progression of tumors in several ways. Cellular senescence is a natural barrier used by cells to respond to stress. The molecular analysis of immortal clones shows alterations, either structural or epigenetic, in the genes involved in cellular senescence. It is thought that these alterations are caused directly by mutating or methylating the genes involved in cellular senescence. Therefore, understanding cellular senescence and how it can be modified by environmental carcinogens may be essential to control the increase in cancer prevalence. In the present work, we explored the role of cellular senescence barrier in the carcinogenic potential of some known carcinogens. We found that most carcinogens tested induce a primary senescent response in diploid mouse embryonic fibroblasts (MEFs) and the clones arising with proliferative capacity contain mutated p53 protein. This primary response of senescence induction is abolished in the presence of the p53 inhibitor, pifithrin-a. Under these conditions, the tumorigenic potential of carcinogens is greatly increased. Upon elimination of pifithrin-a from the media, cellular senescence is restored. Therefore, the first cellular response to a carcinogen is a cell cycle arrest program that may result in a permanent arrest with features of cellular senescence. If there is a concomitant alteration of genes involved in cellular senescence, which promotes cellular immortalization, a further carcinogenic insult may increase the chances of tumorigenesis and a malignant clone may develop.

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Section: Discussionsupporting

confidence: 84%

“…Recently, an in vivo system has been reported, based on the activation of p16INK4a [32], a classic marker activated upon cellular senescence [12,19,33]. The murine strain harbors a knock-in of the luciferase gene into the cdkn2a locus [34].…”

Section: Discussionmentioning

confidence: 99%

Cellular Senescence Controlled by p53 is a Barrier to Environmental Carcinogenesis

Carnero¹

2015

J Carcinog Mutagen

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“…38 Rapid occurrence of senescence has also been found in patients who had undergone irradiation or chemotherapy. 5,39 In the kidney, we and others have previously observed that acute stress, such as experimental AKI by I/R, can trigger a forced development of cellular senescence.…”

Section: Discussionmentioning

confidence: 99%

The impact of autophagy on the development of senescence in primary tubular epithelial cells

et al. 2016

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Autophagy and senescence are 2 distinct pathways that are importantly involved in acute kidney injury and renal repair. Recent data indicate that the 2 processes might be interrelated. To investigate the potential link between autophagy and senescence in the kidney we isolated primary tubular epithelial cells (PTEC) from wild-type mice and monitored the occurrence of cellular senescence during autophagy activation and inhibition. We found that the process of cell isolation and transfer into culture was associated with a strong basal autophagic activation in PTEC. Specific inhibition of autophagy by silencing autophagy-related 5 (Atg5) counteracted the occurrence of senescence hallmarks under baseline conditions. Reduced senescent features were also observed in Atg5 silenced PTEC after g-irradiation and during H-Ras induced oncogenic senescence, but the response was less uniform in these stress models. Senescence inhibition was paralleled by better preservation of a mature epithelial phenotype in PTEC. Interestingly, treatment with rapamycin, which acts as an activator of autophagy, also counteracted the occurrence of senescence features in PTEC. While we interpret the anti-senescent effect of rapamycin as an autophagy-independent effect of mTOR-inhibition, the more specific approach of Atg5 silencing indicates that overactivated autophagy can have pro-senescent effects in PTEC. These results highlight the complex interaction between cell culture dependent stress mechanisms, autophagy and senescence.

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“…Senescence of endothelial cells has also been linked to the pathomechanism of COPD and correlates with telomere dysfunction in these patients [50]. A recent study that used p16INK4 reporter mice to screen for age-promoting effects of environmental pollutants observed the induction of this senescence marker in response to cigarette smoke, suggesting a causal link of cigarette smoke damage and senescence induction [101]. Whether this is part of a protective response of the lung, or causally contributes to the development of obstructive lung disease requires further investigation.…”

Section: Cellular Senescencementioning

confidence: 99%

Hallmarks of the ageing lung

2015

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Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, "dysregulation of the extracellular matrix", which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases. @ERSpublications Hallmarks of ageing are selecting factors for the pathogenesis of COPD, lung cancer and IPF

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p16INK4a reporter mice reveal age-promoting effects of environmental toxicants

Cited by 70 publications

References 34 publications

Cellular Senescence Controlled by p53 is a Barrier to Environmental Carcinogenesis

Cellular Senescence Controlled by p53 is a Barrier to Environmental Carcinogenesis

The impact of autophagy on the development of senescence in primary tubular epithelial cells

Hallmarks of the ageing lung

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