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      mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype

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          Abstract

          Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response but it can also display pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find novel SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2/MAPKAPK2 kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells both in tumour-suppressive and promoting-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses.

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          Most cited references32

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          Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion

          Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells1. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments2. 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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            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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              Is Open Access

              PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse

              PhosphoSitePlus (http://www.phosphosite.org) is an open, comprehensive, manually curated and interactive resource for studying experimentally observed post-translational modifications, primarily of human and mouse proteins. It encompasses 1 30 000 non-redundant modification sites, primarily phosphorylation, ubiquitinylation and acetylation. The interface is designed for clarity and ease of navigation. From the home page, users can launch simple or complex searches and browse high-throughput data sets by disease, tissue or cell line. Searches can be restricted by specific treatments, protein types, domains, cellular components, disease, cell types, cell lines, tissue and sequences or motifs. A few clicks of the mouse will take users to substrate pages or protein pages with sites, sequences, domain diagrams and molecular visualization of side-chains known to be modified; to site pages with information about how the modified site relates to the functions of specific proteins and cellular processes and to curated information pages summarizing the details from one record. PyMOL and Chimera scripts that colorize reactive groups on residues that are modified can be downloaded. Features designed to facilitate proteomic analyses include downloads of modification sites, kinase–substrate data sets, sequence logo generators, a Cytoscape plugin and BioPAX download to enable pathway visualization of the kinase–substrate interactions in PhosphoSitePlus®.
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                Author and article information

                Journal
                100890575
                21417
                Nat Cell Biol
                Nat. Cell Biol.
                Nature cell biology
                1465-7392
                1476-4679
                22 September 2015
                17 August 2015
                September 2015
                01 March 2016
                : 17
                : 9
                : 1205-1217
                Affiliations
                [1 ]Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
                [2 ]Epigenetics Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
                [3 ]Metabolic Signalling Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
                [4 ]Cancer Sciences Unit, Cancer Research UK Centre, Somers Building, University of Southampton, Southampton SO16 6YD, UK.
                [5 ]Division of Molecular Oncology of Solid Tumors, Dept. of Internal Medicine I, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
                [6 ]Proteomics Facility; MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
                [7 ]Birth Defects Research Centre, Neural Development Unit, UCL Institute of Child Health, London, WC1N 1EH, UK
                [8 ]Institute for Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.
                [9 ]Division of Chronic Inflammation and Cancer, German Cancer Research (DKFZ), Heidelberg, Germany.
                [10 ]Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI 48109-2200, USA
                Author notes
                [* ]Corresponding author: jesus.gil@ 123456csc.mrc.ac.uk
                [a]

                Current address: Stem Cell & Regenerative Biology, Genome Institute of Singapore, Singapore 138672

                [b]

                Current address: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ

                Article
                EMS64332
                10.1038/ncb3225
                4589897
                26280535
                3c29ae16-e39a-447a-8f9c-bfdb54c61ad1

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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                Categories
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                Cell biology
                mtor,sasp,senescence,rapamycin,mapkapk2,zfp36l1
                Cell biology
                mtor, sasp, senescence, rapamycin, mapkapk2, zfp36l1

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