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      The Matricellular Protein CCN1/CYR61 Induces Fibroblast Senescence and Restricts Fibrosis in Cutaneous Wound Healing

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      1 , 1 , *
      Nature cell biology

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          Abstract

          Cellular senescence is a recognised mechanism of tumor suppression; however, its contribution to other pathologies is not well understood. We show that the matricellular protein CCN1/CYR61, which is dynamically expressed at sites of wound repair, can induce fibroblast senescence through its cell adhesion receptors, integrin α 6β 1 and heparan sulfate proteoglycans. CCN1 induces DNA damage response and p53 activation, and activates the RAC1-NOX1 complex to induce reactive oxygen species (ROS) generation and ROS-dependent activation of the p16 INK4a/pRb pathway, leading to senescence and concomitant expression of antifibrotic genes. Senescent fibroblasts accumulate in granulation tissues of healing cutaneous wounds and express antifibrotic genes in wild type mice. These processes are obliterated in knockin mice that express a senescence-defective CCN1 mutant, resulting in exacerbated fibrosis. Topical application of CCN1 protein to wounds reverses these defects. Thus, fibroblast senescence is a CCN1-dependent wound healing response in cutaneous injury, functioning to curb fibrosis during tissue repair.

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          Most cited references46

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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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            The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus.

            The bmi-1 gene was first isolated as an oncogene that cooperates with c-myc in the generation of mouse lymphomas. We subsequently identified Bmi-1 as a transcriptional repressor belonging to the mouse Polycomb group. The Polycomb group comprises an important, conserved set of proteins that are required to maintain stable repression of specific target genes, such as homeobox-cluster genes, during development. In mice, the absence of bmi-1 expression results in neurological defects and severe proliferative defects in lymphoid cells, whereas bmi-1 overexpression induces lymphomas. Here we show that bmi-1-deficient primary mouse embryonic fibroblasts are impaired in progression into the S phase of the cell cycle and undergo premature senescence. In these fibroblasts and in bmi-1-deficient lymphocytes, the expression of the tumour suppressors p16 and p19Arf, which are encoded by ink4a, is raised markedly. Conversely, overexpression of bmi-1 allows fibroblast immortalization, downregulates expression of p16 and p19Arf and, in combination with H-ras, leads to neoplastic transformation. Removal of ink4a dramatically reduces the lymphoid and neurological defects seen in bmi-1-deficient mice, indicating that ink4a is a critical in vivo target for Bmi-1. Our results connect transcriptional repression by Polycomb-group proteins with cell-cycle control and senescence.
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              Senescence-messaging secretome: SMS-ing cellular stress.

              Oncogene-induced cellular senescence constitutes a strong anti-proliferative response, which can be set in motion following either oncogene activation or loss of tumour suppressor signalling. It serves to limit the expansion of early neoplastic cells and as such is a potent cancer-protective response to oncogenic events. Recently emerging evidence points to a crucial role in oncogene-induced cellular senescence for the 'senescence-messaging secretome' or SMS, setting the stage for cross-talk between senescent cells and their environment. How are such signals integrated into a coordinated response and what are the implications of this unexpected finding?
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                Author and article information

                Journal
                100890575
                21417
                Nat Cell Biol
                Nature cell biology
                1465-7392
                1476-4679
                24 May 2010
                6 June 2010
                July 2010
                1 January 2011
                : 12
                : 7
                : 676-685
                Affiliations
                [1 ]Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 S. Ashland Avenue, Chicago, Illinois 60607-7170, USA
                Author notes

                AUTHOR CONTRIBUTIONS J.-I.J. conducted the experiments; J.-I.J. and L.F.L. designed the experimental plan, analyzed the data, and wrote the paper.

                [* ]Corresponding author: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, IL 60607. Tel: 312-996-6978; Fax: 312-996-7034. LFLau@ 123456uic.edu
                Article
                nihpa201997
                10.1038/ncb2070
                2919364
                20526329
                b525a853-d530-4053-9505-739b8cc6ab90

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                History
                Funding
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Cancer Institute : NCI
                Award ID: R01 GM078492-03S1 ||GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Cancer Institute : NCI
                Award ID: R01 GM078492-03 ||GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA046565-19 ||CA
                Categories
                Article

                Cell biology
                Cell biology

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