Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts

Robles, Steven J.; Adami, Guy R.

doi:10.1038/sj.onc.1201862

Cited by 433 publications

(322 citation statements)

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“…Retention of c-Fos inducibility was specific to hydrogen-peroxide-induced senescence. Cells induced to senesce by treatment with the DNA-damaging agent bleomycin 12 or through overexpression of p14 ARF (ref. 13) lost serum-inducible c-Fos expression (Fig.…”

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confidence: 99%

Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts

et al. 2003

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Most mammalian cells do not divide indefinitely, owing to a process termed replicative senescence. In human cells, replicative senescence is caused by telomere shortening, but murine cells senesce despite having long stable telomeres 1 . Here, we show that the phenotypes of senescent human fibroblasts and mouse embryonic fibroblasts (MEFs) differ under standard culture conditions, which include 20% oxygen. MEFs did not senesce in physiological (3%) oxygen levels, but underwent a spontaneous event that allowed indefinite proliferation in 20% oxygen. The proliferation and cytogenetic profiles of DNA repair-deficient MEFs suggested that DNA damage limits MEF proliferation in 20% oxygen. Indeed, MEFs accumulated more DNA damage in 20% oxygen than 3% oxygen, and more damage than human fibroblasts in 20% oxygen. Our results identify oxygen sensitivity as a critical difference between mouse and human cells, explaining their proliferative differences in culture, and possibly their different rates of cancer and ageing.Replicative senescence limits the proliferation of many cell types in culture and in vivo 2 .Human cells senesce replicatively largely because telomeres -DNA structures that cap chromosome ends -shorten and malfunction when replicated in the absence of telomerase, which most human cells do not express 1 . Senescent cells adopt a distinctive morphology and pattern of gene expression 2,3 , a phenotype also induced by telomere-independent events 2,4 such as DNA damage and activation of certain oncogenes. The senescence response is thought to suppress cancer 2 .MEFs are used widely in the study of replicative senescence, despite notable differences between human and rodent cells 1,2 . MEFs spontaneously overcome replicative senescence (immortalization) 5,6 , whereas human fibroblasts rarely do so. Moreover, MEF senescence relies predominantly on the p19 ARF /p53 tumour suppressor pathway, whereas human fibroblasts require loss of both p53 and retinoblastoma (Rb) tumour suppressor functions for Correspondence should be addressed to: J.C. (jcampisi@lbl.gov). Note: Supplementary Information is available on the Nature Cell Biology website. COMPETING FINANCIAL INTERESTSThe authors declare that they have no competing financial interests. Here, we compared the phenotypes of senescent mouse and human fibroblasts. We cultured MEFs from C57Bl/6 (or FVB; data not shown) mice under standard conditions, which include atmospheric (20%) oxygen (Fig. 1a). As expected 5 , the cells grew well for approximately 1 week (2-3 population doublings) before proliferation began to decline. After 4-5 weeks (8-10 population doublings), the cultures senesced (arrow), showing no change in cell number for more than 1 week and a senescent morphology. Proliferation eventually resumed, owing to outgrowth of immortal variants 5 . HHS Public AccessWe monitored the capacity for DNA synthesis at each passage by labelling cells with 3 Hthymidine for 3 days and counting radiolabelled nuclei. As reported 9 , the percentage of labelled nuclei d...

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Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts

et al. 2003

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“…Much evidence exists supporting a link between DNA damage, p16 expression and cellular senescence. For example, in normal human fibroblasts and tumor cells, DNA double-strand breaks lead to increased p16 expression and senescence (Robles and Adami, 1998;te Poele et al, 2002). To examine whether p16 expression can be a major factor to induce senescence in Aurora A overexpressing cells, we infected the immortalized mouse fibroblasts derived from CAG-CAT-Aurora A mice, which do not express p16, with p16-expressing adenovirus and/or AxCANCre virus, which induces Aurora A expression and tested senescence of those cells with an SA-b-gal assay.…”

Section: Discussionmentioning

confidence: 99%

Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice

et al. 2008

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Aurora A mitotic kinase is frequently overexpressed in various human cancers and is widely considered to be an oncoprotein. However, the cellular contexts in which Aurora A induces malignancy in vivo are still unclear. We previously reported a mouse model in which overexpression of human Aurora A in the mammary gland leads to small hyperplastic changes but not malignancy because of the induction of p53-dependent apoptosis. To study the additional factors required for Aurora A-associated tumorigenesis, we generated a new Aurora A overexpression mouse model that lacks p53. We present evidence here that Aurora A overexpression in primary mouse embryonic fibroblasts (MEFs) that lack p53 overrides postmitotic checkpoint and leads to the formation of multinucleated polyploid cells. Induction of Aurora A overexpression in the mammary glands of p53-deficient mice resulted in development of precancerous lesions that were histologically similar to atypical ductal hyperplasia in human mammary tissue and showed increased cellular senescence and p16 expression. We further observed DNA damage in p53-deficient primary MEFs after Aurora A overexpression. Our results suggest that Aurora A overexpression in mammary glands is insufficient for the development of malignant tumors in p53-deficient mice because of the induction of cellular senescence. Both p53 and p16 are critical in preventing mammary gland tumorigenesis in the Aurora A overexpression mouse model.

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“…These events include DNA damage (DiLeonardo et al, 1994;Chen et al, 1995;Robles and Adami, 1998), as well as perturbations to chromatin organization (Ogryzko et al, 1996;Jacobs et al, 1999;Itahana et al, 2003;Narita et al, 2003). They also include the expression of certain oncogenes (Serrano et al, 1997;Zhu et al, 1998;Dimri et al, 2000) that deliver supraphysiological mitogenic signals to cells, and the overexpression of certain tumor suppressor genes (Sugrue et al, 1997;McConnell et al, 1998;Dai and Enders, 2000;Dimri et al, 2000;Beausejour et al, 2003).…”

Section: Causes Of Senescencementioning

confidence: 99%

Aging, tumor suppression and cancer: high wire-act!

Campisi

2005

Mechanisms of Ageing and Development

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Evolutionary theory holds that aging is a consequence of the declining force of natural selection with age. We discuss here the evidence that among the causes of aging in complex multicellular organisms, such as mammals, is the antagonistically pleiotropic effects of the cellular responses that protect the organism from cancer. Cancer is relatively rare in young mammals, owing in large measure to the activity of tumor suppressor mechanisms. These mechanisms either protect the genome from damage and/or mutations, or they elicit cellular responsesapoptosis or senescence-that eliminate or prevent the proliferation of somatic cells at risk for neoplastic transformation. We focus here on the senescence response, reviewing its causes, regulation and effects. In addition, we describe recent data that support the idea that both senescence and apoptosis may indeed be the double-edged swords predicted by the evolutionary hypothesis of antagonistic pleiotropyprotecting organisms from cancer early in life, but promoting aging phenotypes, including late life cancer, in older organisms. # 2004 Published by Elsevier Ireland Ltd.

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Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts

Cited by 433 publications

References 53 publications

Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts

Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts

Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice

Aging, tumor suppression and cancer: high wire-act!

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