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

Autor: Karmveer Singh, Andre Burkovski, Pallab Maity, Thomas Wirth, Meinhard Wlaschek, Patrick Meyer, Filipa F. Ferreira, Karin Scharffetter-Kochanek, Linda Krug, Christoph Müssel, Julian D. Schwab, Hans A. Kestler, Harald J. Maier
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Aging
Physiology
Regulator
Gene regulatory network
Gene Expression
Biochemistry
Mice
Animal Cells
Medicine and Health Sciences
Biochemical Simulations
Cell Cycle and Cell Division
Biology (General)
Cells
Cultured
Cellular Senescence
Connective Tissue Cells
Ecology
3. Good health
Cell biology
Nucleic acids
Computational Theory and Mathematics
Cell Processes
Connective Tissue
Modeling and Simulation
Cellular Types
Anatomy
Network Analysis
Research Article
Signal Transduction
Senescence
Computer and Information Sciences
QH301-705.5
DNA damage
Biology
Models
Biological
03 medical and health sciences
Cellular and Molecular Neuroscience
Gene interaction
Genetics
Animals
Gene Regulation
Computer Simulation
Molecular Biology
Transcription factor
Ecology
Evolution
Behavior and Systematics
Gene knockout
Secretion
Biology and life sciences
Interleukin-6
fungi
Interleukin-8
Computational Biology
DNA
Cell Biology
Fibroblasts
NFKB1
030104 developmental biology
Biological Tissue
Physiological Processes
Organism Development
Developmental Biology
Zdroj: PLoS Computational Biology
PLoS Computational Biology, Vol 13, Iss 12, p e1005741 (2017)
ISSN: 1553-7358
1553-734X
Popis: 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-κB 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-κB 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-κB, giving access to possible therapy targets for SASP-accompanied diseases.
Author summary The senescence associated secretory phenotype is developed by cells undergoing permanent cell cycle arrest. This phenotype is characterized by the secretion of a variety of factors that facilitate tissue breakdown and inflammation and is therefore theorized to, in part, be causal for aging and age-related diseases. In recent years the SASP has been implicated in a variety of chronic inflammatory diseases. Due to these advances, it is imperative to better understand the dynamics of this cellular phenotype and to find ways to disrupt it. We have developed a Boolean network incorporating the major signaling pathways of the SASP that allows us to specifically investigate interactions of the pathways and genes involved. We validated our model by reliably reproducing published data on the SASP. We utilized our model to uncover components that directly control the detrimental effects of the senescence associated secretory phenotype that are largely caused by IL-6 and IL-8, two major factors of the SASP in establishing and spreading senescence as well as causing local inflammation. In subsequent in-vitro experiments, we were able to verify our computational results and could suggest NEMO as one potential target for therapy of SASP-related diseases.
Databáze: OpenAIRE
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