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      Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion

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          Abstract

          Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells 1. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments 2. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signaling, usually associated with senescence, not after transient DNA damage responses (DDR). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Further, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell cycle checkpoints and DNA repair, a novel and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.

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          Most cited references 17

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          Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.

          Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.
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            Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions.

            DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive. We analysed a panel of human lung hyperplasias, all of which retained wild-type p53 genes and had no signs of gross chromosomal instability, and found signs of a DNA damage response, including histone H2AX and Chk2 phosphorylation, p53 accumulation, focal staining of p53 binding protein 1 (53BP1) and apoptosis. Progression to carcinoma was associated with p53 or 53BP1 inactivation and decreased apoptosis. A DNA damage response was also observed in dysplastic nevi and in human skin xenografts, in which hyperplasia was induced by overexpression of growth factors. Both lung and experimentally-induced skin hyperplasias showed allelic imbalance at loci that are prone to DNA double-strand break formation when DNA replication is compromised (common fragile sites). We propose that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations.
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              Chemokine signaling via the CXCR2 receptor reinforces senescence.

              Cells enter senescence, a state of stable proliferative arrest, in response to a variety of cellular stresses, including telomere erosion, DNA damage, and oncogenic signaling, which acts as a barrier against malignant transformation in vivo. To identify genes controlling senescence, we conducted an unbiased screen for small hairpin RNAs that extend the life span of primary human fibroblasts. Here, we report that knocking down the chemokine receptor CXCR2 (IL8RB) alleviates both replicative and oncogene-induced senescence (OIS) and diminishes the DNA-damage response. Conversely, ectopic expression of CXCR2 results in premature senescence via a p53-dependent mechanism. Cells undergoing OIS secrete multiple CXCR2-binding chemokines in a program that is regulated by the NF-kappaB and C/EBPbeta transcription factors and coordinately induce CXCR2 expression. CXCR2 upregulation is also observed in preneoplastic lesions in vivo. These results suggest that senescent cells activate a self-amplifying secretory network in which CXCR2-binding chemokines reinforce growth arrest.
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                Author and article information

                Journal
                100890575
                21417
                Nat Cell Biol
                Nature cell biology
                1465-7392
                1476-4679
                27 April 2009
                13 July 2009
                August 2009
                1 February 2010
                : 11
                : 8
                : 973-979
                Affiliations
                [1 ] Lawrence Berkeley National Laboratory, One Cyclotron Road, Berkeley, CA 94720 USA
                [2 ] Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94545 USA
                [3 ] Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720 USA
                Author notes
                [4]

                Department of Molecular Biology, Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands

                [5]

                Royal Free & University College Medical School, Gower Street, London WC1E 6BT, England

                [6]

                Program in Gene Function and Expression, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA, 01605 USA

                Article
                nihpa112909
                10.1038/ncb1909
                2743561
                19597488
                Funding
                Funded by: National Institute on Aging : NIA
                Award ID: P30 AG025708-04 ||AG
                Funded by: National Institute on Aging : NIA
                Award ID: P01 AG017242-100003 ||AG
                Categories
                Article

                Cell biology

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