Feedback between p21 and reactive oxygen production is necessary for cell senescence

João F. Passos, Glyn Nelson, Chunfang Wang, Torsten Richter, Cedric Simillion, Carole J. Proctor, Satomi Miwa, Sharon Olijslagers, Jennifer Hallinan, Anil Wipat, Gabriele Saretzki, Karl Lenhard Rudolph, Tom B.L. Kirkwood, Thomas Von Zglinicki

Research output: Contribution to journalArticle

421 Scopus citations

Abstract

Cellular senescencethe permanent arrest of cycling in normally proliferating cells such as fibroblastscontributes both to age-related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of deep cellular senescence. The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFΒ. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.

Original languageEnglish (US)
Article number347
JournalMolecular Systems Biology
Volume6
DOIs
StatePublished - 2010

Keywords

  • Aging
  • Cell senescence
  • DNA damage foci
  • Mitochondria
  • Reactive oxygen

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)
  • Applied Mathematics

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    Passos, J. F., Nelson, G., Wang, C., Richter, T., Simillion, C., Proctor, C. J., Miwa, S., Olijslagers, S., Hallinan, J., Wipat, A., Saretzki, G., Rudolph, K. L., Kirkwood, T. B. L., & Von Zglinicki, T. (2010). Feedback between p21 and reactive oxygen production is necessary for cell senescence. Molecular Systems Biology, 6, [347]. https://doi.org/10.1038/msb.2010.5