4.6 Article

A model of the onset of the senescence associated secretory phenotype after DNA damage induced senescence

Journal

PLOS COMPUTATIONAL BIOLOGY
Volume 13, Issue 12, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pcbi.1005741

Keywords

-

Funding

  1. German Research Foundation (DFG) [SCHA411/15-2, KF0142]
  2. Graduate Training Centre Cellular and Molecular Mechanisms in Ageing (CEMMA) [GRK 1789]
  3. Ministerium fur Wissenschaft, Forschung und Kunst Baden-Wurttemberg, Germany [CRC1149, FKZ0315894A]
  4. European Community's Seventh Framework Programme (FP7) [n602783]
  5. DFG [SFB 1074]
  6. German Federal Ministry of Education and Research (BMBF) [0315894A, 01ZX1407A]

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Cells and tissues are exposed to stress from numerous sources. Senescence is a protective mechanism that prevents malignant tissue changes and constitutes a fundamental mechanism of aging. It can be accompanied by a senescence associated secretory phenotype ( SASP) that causes chronic inflammation. We present a Boolean network model-based gene regulatory network of the SASP, incorporating published gene interaction data. The simulation results describe current biological knowledge. The model predicts different in-silico knockouts that prevent key SASP-mediators, IL-6 and IL-8, from getting activated upon DNA damage. The NF-kappa B Essential Modulator (NEMO) was the most promising in-silico knockout candidate and we were able to show its importance in the inhibition of IL-6 and IL-8 following DNA-damage in murine dermal fibroblasts in-vitro. We strengthen the speculated regulator function of the NF-kappa B signaling pathway in the onset and maintenance of the SASP using in-silico and in-vitro approaches. We were able to mechanistically show, that DNA damage mediated SASP triggering of IL-6 and IL-8 is mainly relayed through NF-kappa B, giving access to possible therapy targets for SASP-accompanied diseases.

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