A Model for p38MAPK-Induced Astrocyte Senescence
Experimental evidence indicates that aging leads to accumulation of senescent cells in tissues and they develop a secretory phenotype (also known as SASP, for senescence-associated secretory phenotype) that can contribute to chronic inflammation and diseases. Recent results have showed that markers...
| Main Authors: | , , |
|---|---|
| Format: | Online |
| Language: | English |
| Published: |
Public Library of Science
2015
|
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425668/ |
| id |
pubmed-4425668 |
|---|---|
| recordtype |
oai_dc |
| spelling |
pubmed-44256682015-05-21 A Model for p38MAPK-Induced Astrocyte Senescence Mombach, José C. M. Vendrusculo, Bruno Bugs, Cristhian A. Research Article Experimental evidence indicates that aging leads to accumulation of senescent cells in tissues and they develop a secretory phenotype (also known as SASP, for senescence-associated secretory phenotype) that can contribute to chronic inflammation and diseases. Recent results have showed that markers of senescence in astrocytes from aged brains are increased in brains with Alzheimer’s disease. These studies strongly involved the stress kinase p38MAPK in the regulation of the secretory phenotype of astrocytes, yet the molecular mechanisms underlying the onset of senescence and SASP activation remain unclear. In this work, we propose a discrete logical model for astrocyte senescence determined by the level of DNA damage (reparable or irreparable DNA strand breaks) where the kinase p38MAPK plays a central role in the regulation of senescence and SASP. The model produces four alternative stable states: proliferation, transient cycle arrest, apoptosis and senescence (and SASP) computed from its inputs representing DNA damages. Perturbations of the model were performed through gene gain or loss of functions and compared with results concerning cultures of normal and mutant astrocytes showing agreement in most cases. Moreover, the model allows some predictions that remain to be tested experimentally. Public Library of Science 2015-05-08 /pmc/articles/PMC4425668/ /pubmed/25954815 http://dx.doi.org/10.1371/journal.pone.0125217 Text en © 2015 Mombach 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Mombach, José C. M. Vendrusculo, Bruno Bugs, Cristhian A. |
| spellingShingle |
Mombach, José C. M. Vendrusculo, Bruno Bugs, Cristhian A. A Model for p38MAPK-Induced Astrocyte Senescence |
| author_facet |
Mombach, José C. M. Vendrusculo, Bruno Bugs, Cristhian A. |
| author_sort |
Mombach, José C. M. |
| title |
A Model for p38MAPK-Induced Astrocyte Senescence |
| title_short |
A Model for p38MAPK-Induced Astrocyte Senescence |
| title_full |
A Model for p38MAPK-Induced Astrocyte Senescence |
| title_fullStr |
A Model for p38MAPK-Induced Astrocyte Senescence |
| title_full_unstemmed |
A Model for p38MAPK-Induced Astrocyte Senescence |
| title_sort |
model for p38mapk-induced astrocyte senescence |
| description |
Experimental evidence indicates that aging leads to accumulation of senescent cells in tissues and they develop a secretory phenotype (also known as SASP, for senescence-associated secretory phenotype) that can contribute to chronic inflammation and diseases. Recent results have showed that markers of senescence in astrocytes from aged brains are increased in brains with Alzheimer’s disease. These studies strongly involved the stress kinase p38MAPK in the regulation of the secretory phenotype of astrocytes, yet the molecular mechanisms underlying the onset of senescence and SASP activation remain unclear. In this work, we propose a discrete logical model for astrocyte senescence determined by the level of DNA damage (reparable or irreparable DNA strand breaks) where the kinase p38MAPK plays a central role in the regulation of senescence and SASP. The model produces four alternative stable states: proliferation, transient cycle arrest, apoptosis and senescence (and SASP) computed from its inputs representing DNA damages. Perturbations of the model were performed through gene gain or loss of functions and compared with results concerning cultures of normal and mutant astrocytes showing agreement in most cases. Moreover, the model allows some predictions that remain to be tested experimentally. |
| publisher |
Public Library of Science |
| publishDate |
2015 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425668/ |
| _version_ |
1613221363664814080 |