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

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. W...

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Autores principales: Meyer, Patrick, Maity, Pallab, Burkovski, Andre, Schwab, Julian, Müssel, Christoph, Singh, Karmveer, Ferreira, Filipa F., Krug, Linda, Maier, Harald J., Wlaschek, Meinhard, Wirth, Thomas, Kestler, Hans A., Scharffetter-Kochanek, Karin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730191/
https://www.ncbi.nlm.nih.gov/pubmed/29206223
http://dx.doi.org/10.1371/journal.pcbi.1005741
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author Meyer, Patrick
Maity, Pallab
Burkovski, Andre
Schwab, Julian
Müssel, Christoph
Singh, Karmveer
Ferreira, Filipa F.
Krug, Linda
Maier, Harald J.
Wlaschek, Meinhard
Wirth, Thomas
Kestler, Hans A.
Scharffetter-Kochanek, Karin
author_facet Meyer, Patrick
Maity, Pallab
Burkovski, Andre
Schwab, Julian
Müssel, Christoph
Singh, Karmveer
Ferreira, Filipa F.
Krug, Linda
Maier, Harald J.
Wlaschek, Meinhard
Wirth, Thomas
Kestler, Hans A.
Scharffetter-Kochanek, Karin
author_sort Meyer, Patrick
collection PubMed
description 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.
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spelling pubmed-57301912017-12-22 A model of the onset of the senescence associated secretory phenotype after DNA damage induced senescence Meyer, Patrick Maity, Pallab Burkovski, Andre Schwab, Julian Müssel, Christoph Singh, Karmveer Ferreira, Filipa F. Krug, Linda Maier, Harald J. Wlaschek, Meinhard Wirth, Thomas Kestler, Hans A. Scharffetter-Kochanek, Karin PLoS Comput Biol Research Article 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. Public Library of Science 2017-12-04 /pmc/articles/PMC5730191/ /pubmed/29206223 http://dx.doi.org/10.1371/journal.pcbi.1005741 Text en © 2017 Meyer et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Meyer, Patrick
Maity, Pallab
Burkovski, Andre
Schwab, Julian
Müssel, Christoph
Singh, Karmveer
Ferreira, Filipa F.
Krug, Linda
Maier, Harald J.
Wlaschek, Meinhard
Wirth, Thomas
Kestler, Hans A.
Scharffetter-Kochanek, Karin
A model of the onset of the senescence associated secretory phenotype after DNA damage induced senescence
title A model of the onset of the senescence associated secretory phenotype after DNA damage induced senescence
title_full A model of the onset of the senescence associated secretory phenotype after DNA damage induced senescence
title_fullStr A model of the onset of the senescence associated secretory phenotype after DNA damage induced senescence
title_full_unstemmed A model of the onset of the senescence associated secretory phenotype after DNA damage induced senescence
title_short A model of the onset of the senescence associated secretory phenotype after DNA damage induced senescence
title_sort model of the onset of the senescence associated secretory phenotype after dna damage induced senescence
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730191/
https://www.ncbi.nlm.nih.gov/pubmed/29206223
http://dx.doi.org/10.1371/journal.pcbi.1005741
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