Publication

The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4

Kang, C., Xu, Q., Martin, T. D., Li, M. Z., Demaria, M., Aron, L., Lu, T., Yankner, B. A., Campisi, J. & Elledge, S. J., 25-Sep-2015, In : Science. 349, 6255, p. aaa5612

Research output: Contribution to journalArticleAcademicpeer-review

  • Chanhee Kang
  • Qikai Xu
  • Timothy D Martin
  • Mamie Z Li
  • Marco Demaria
  • Liviu Aron
  • Tao Lu
  • Bruce A Yankner
  • Judith Campisi
  • Stephen J Elledge

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.

Original languageEnglish
Pages (from-to)aaa5612
JournalScience
Volume349
Issue number6255
Publication statusPublished - 25-Sep-2015
Externally publishedYes

    Keywords

  • Aging, Animals, Ataxia Telangiectasia Mutated Proteins, Autophagy, Brain, Cell Aging, Cell Cycle, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16, DNA Damage, Fibroblasts, GATA4 Transcription Factor, Gene Expression Profiling, Humans, Inflammation, Interleukin-1alpha, Mice, Mice, Inbred C57BL, MicroRNAs, NF-kappa B, Phenotype, Promoter Regions, Genetic, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Tumor Suppressor Protein p53

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