Nuclear Translocation of Argonaute 2 in Cytokine-Induced Senescence

Autor: Maximilian Rentschler, Yan Chen, Jana Pahl, Laura Soria-Martinez, Heidi Braumüller, Ellen Brenner, Oliver Bischof, Martin Röcken, Thomas Wieder
Přispěvatelé: Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe labellisée Ligue contre le Cancer, This work was supported by the Wilhelm Sander Foundation (2012.056.3 to M.R.), German Cancer Aid (application numbers 109037 and 110664 to M.R.), and German Research Association (TRR-SFB 156, DFG RO 764/14-1 and DFG RO 764/15-2 to M.R. and DFG WI 1279/4-1 to T.W.). The group of O.B. is supported by grants from ANR-BMFT, Fondation ARC pour la recherche sur le Cancer, INSERM, and the National Cancer Institute of the National Institutes of Health under Award Number R01CA136533. O.B. is a CNRS Research Director DR2.We acknowledge support by Deutsche Forschungsgemeinschaft and open Access Publishing Fund of University of Tübingen, Martin Röckenand Thomas Wieder share senior authorship. The authors would like to thank S. Weidemann and V. Galinat for expert technical assistance., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Bischof, Oliver
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Cellular Physiology and Biochemistry
Cellular Physiology and Biochemistry, 2018, 51 (3), pp.1103-1118. ⟨10.1159/000495490⟩
Cellular Physiology and Biochemistry, Karger, 2018, 51 (3), pp.1103-1118. ⟨10.1159/000495490⟩
Cellular Physiology and Biochemistry, Vol 51, Iss 3, Pp 1103-1118 (2018)
ISSN: 1015-8987
1421-9778
DOI: 10.1159/000495490⟩
Popis: International audience; BACKGROUND/AIMS:Cellular senescence, or permanent growth arrest, is known as an effective tumor suppressor mechanism that can be induced by different stressors, such as oncogenes, chemotherapeutics or cytokine cocktails. Previous studies demonstrated that the growth-repressing state of oncogene-induced senescent cells depends on argonaute protein 2 (Ago2)-mediated transcriptional gene silencing and Ago2/Rb corepression of E2F-dependent cell cycle genes. Cytokine-induced senescence (CIS) likewise depends on activation of the p16Ink4a/Rb pathway, and consecutive inactivation of the E2F family of transcription factors. In the present study, we therefore analyzed the role of Ago2 in CIS.METHODS:Human cancer cell lines were treated with interferon-gamma (IFN-γ) and tumor necrosis factor (TNF) to induce senescence. Senescence was determined by growth assays and measurement of senescence-associated β-galactosidase (SA-β-gal) activity, Ago2 translocation by Ago2/ Ki67 immunofluorescence staining and western blot analysis, and gene transcription by quantitative polymerase chain reaction (qPCR).RESULTS:IFN-γ and TNF permanently stopped cell proliferation and time-dependently increased SA-β-gal activity. After 24 - 48 h of cytokine treatment, Ago2 translocated from the cytoplasm into the nucleus of Ki67-negative cells, an effect which was shown to be reversible. Importantly, the proinflammatory cytokine cocktail suppressed Ago2-regulated cell cycle control genes, and siRNA-mediated depletion of Ago2 interfered with cytokine-induced growth inhibition.CONCLUSION:IFN-γ and TNF induce a stable cell cycle arrest of cancer cells that is accompanied by a fast nuclear Ago2 translocation and repression of Ago2-regulated cell cycle control genes. As Ago2 downregulation impairs cytokine-induced growth regulation, Ago2 may contribute to tissue homeostasis in human cancers.
Databáze: OpenAIRE
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