title: The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.
abstract: Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins. A striking feature of senescence is the senescence-associated secretory phenotype (SASP), a pro-inflammatory response linked to tumor promotion and aging. We have identified the transcription factor GATA4 as a senescence and SASP regulator. GATA4 is stabilized in cells undergoing senescence and is required for the SASP. Normally, GATA4 is degraded by p62-mediated selective autophagy, but this regulation is suppressed during senescence, thereby stabilizing GATA4. GATA4 in turn activates the transcription factor NF-κB to initiate the SASP and facilitate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a). GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.
authors.affiliation: Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Chanhee
authors.initials: C
authors.lastname: Kang
authors.affiliation: Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Qikai
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Martin
authors.affiliation: Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Mamie Z
authors.initials: MZ
authors.lastname: Li
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Demaria
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Liviu
authors.initials: L
authors.lastname: Aron
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Yankner
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
authors.affiliation: Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA. selledge@genetics.med.harvard.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004249:DNA Damage; D005347:Fibroblasts; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; C508584:IL1A protein, human; D053582:Interleukin-1alpha; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C414202:TRAF3IP2 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D016159:Tumor Suppressor Protein p53; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins