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SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes
The mechanism by which p53 suppresses tumorigenesis remains poorly understood. In the context of aberrant activation of the JAK/STAT5 pathway, SOCS1 is required for p53 activation and the regulation of cellular senescence. In order to identify p53 target genes acting during the senescence response t...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680560/ https://www.ncbi.nlm.nih.gov/pubmed/29081404 http://dx.doi.org/10.18632/aging.101306 |
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author | Saint-Germain, Emmanuelle Mignacca, Lian Vernier, Mathieu Bobbala, Diwakar Ilangumaran, Subburaj Ferbeyre, Gerardo |
author_facet | Saint-Germain, Emmanuelle Mignacca, Lian Vernier, Mathieu Bobbala, Diwakar Ilangumaran, Subburaj Ferbeyre, Gerardo |
author_sort | Saint-Germain, Emmanuelle |
collection | PubMed |
description | The mechanism by which p53 suppresses tumorigenesis remains poorly understood. In the context of aberrant activation of the JAK/STAT5 pathway, SOCS1 is required for p53 activation and the regulation of cellular senescence. In order to identify p53 target genes acting during the senescence response to oncogenic STAT5A, we characterized the transcriptome of STAT5A-expressing cells after SOCS1 inhibition. We identified a set of SOCS1-dependent p53 target genes that include several secreted proteins and genes regulating oxidative metabolism and ferroptosis. Exogenous SOCS1 was sufficient to regulate the expression of p53 target genes and sensitized cells to ferroptosis. This effect correlated with the ability of SOCS1 to reduce the expression of the cystine transporter SLC7A11 and the levels of glutathione. SOCS1 and SOCS1-dependent p53 target genes were induced during the senescence response to oncogenic STAT5A, RasV12 or the tumor suppressor PML. However, while SOCS1 sensitized cells to ferroptosis neither RasV12 nor STAT5A mimicked the effect. Intriguingly, PML turned cells highly resistant to ferroptosis. The results indicate different susceptibilities to ferroptosis in senescent cells depending on the trigger and suggest the possibility of killing senescent cells by inhibiting pathways that mediate ferroptosis resistance. |
format | Online Article Text |
id | pubmed-5680560 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-56805602017-11-18 SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes Saint-Germain, Emmanuelle Mignacca, Lian Vernier, Mathieu Bobbala, Diwakar Ilangumaran, Subburaj Ferbeyre, Gerardo Aging (Albany NY) Research Paper The mechanism by which p53 suppresses tumorigenesis remains poorly understood. In the context of aberrant activation of the JAK/STAT5 pathway, SOCS1 is required for p53 activation and the regulation of cellular senescence. In order to identify p53 target genes acting during the senescence response to oncogenic STAT5A, we characterized the transcriptome of STAT5A-expressing cells after SOCS1 inhibition. We identified a set of SOCS1-dependent p53 target genes that include several secreted proteins and genes regulating oxidative metabolism and ferroptosis. Exogenous SOCS1 was sufficient to regulate the expression of p53 target genes and sensitized cells to ferroptosis. This effect correlated with the ability of SOCS1 to reduce the expression of the cystine transporter SLC7A11 and the levels of glutathione. SOCS1 and SOCS1-dependent p53 target genes were induced during the senescence response to oncogenic STAT5A, RasV12 or the tumor suppressor PML. However, while SOCS1 sensitized cells to ferroptosis neither RasV12 nor STAT5A mimicked the effect. Intriguingly, PML turned cells highly resistant to ferroptosis. The results indicate different susceptibilities to ferroptosis in senescent cells depending on the trigger and suggest the possibility of killing senescent cells by inhibiting pathways that mediate ferroptosis resistance. Impact Journals LLC 2017-10-28 /pmc/articles/PMC5680560/ /pubmed/29081404 http://dx.doi.org/10.18632/aging.101306 Text en Copyright: © 2017 Saint-Germain et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper Saint-Germain, Emmanuelle Mignacca, Lian Vernier, Mathieu Bobbala, Diwakar Ilangumaran, Subburaj Ferbeyre, Gerardo SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes |
title | SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes |
title_full | SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes |
title_fullStr | SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes |
title_full_unstemmed | SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes |
title_short | SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes |
title_sort | socs1 regulates senescence and ferroptosis by modulating the expression of p53 target genes |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680560/ https://www.ncbi.nlm.nih.gov/pubmed/29081404 http://dx.doi.org/10.18632/aging.101306 |
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