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ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence
Activated Ras oncogene induces DNA-damage response by triggering reactive oxygen species (ROS) production and this is critical for oncogene-induced senescence. Until now, little connections between oncogene expression, ROS-generating NADPH oxidases and DNA-damage response have emerged from different...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307059/ https://www.ncbi.nlm.nih.gov/pubmed/21841825 http://dx.doi.org/10.1038/onc.2011.327 |
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author | Weyemi, U Lagente-Chevallier, O Boufraqech, M Prenois, F Courtin, F Caillou, B Talbot, M Dardalhon, M Al Ghuzlan, A Bidart, J-M Schlumberger, M Dupuy, C |
author_facet | Weyemi, U Lagente-Chevallier, O Boufraqech, M Prenois, F Courtin, F Caillou, B Talbot, M Dardalhon, M Al Ghuzlan, A Bidart, J-M Schlumberger, M Dupuy, C |
author_sort | Weyemi, U |
collection | PubMed |
description | Activated Ras oncogene induces DNA-damage response by triggering reactive oxygen species (ROS) production and this is critical for oncogene-induced senescence. Until now, little connections between oncogene expression, ROS-generating NADPH oxidases and DNA-damage response have emerged from different studies. Here we report that H-RasV12 positively regulates the NADPH oxidase system NOX4-p22(phox) that produces H(2)O(2). Knocking down the NADPH oxidase with small interference RNA decreases H-RasV12-induced DNA-damage response detected by γ-H2A.X foci analysis. Using HyPer, a specific probe for H(2)O(2), we detected an increase in H(2)O(2) in the nucleus correlated with NOX4-p22(phox) perinuclear localization. DNA damage response can be caused not only by H-RasV12-driven accumulation of ROS but also by a replicative stress due to a sustained oncogenic signal. Interestingly, NOX4 downregulation by siRNA abrogated H-RasV12 regulation of CDC6 expression, an essential regulator of DNA replication. Moreover, senescence markers, such as senescence-associated heterochromatin foci, PML bodies, HP1β foci and p21 expression, induced under H-RasV12 activation were decreased with NOX4 inactivation. Taken together, our data indicate that NADPH oxidase NOX4 is a critical mediator in oncogenic H-RasV12-induced DNA-damage response and subsequent senescence. |
format | Online Article Text |
id | pubmed-3307059 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-33070592012-03-19 ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence Weyemi, U Lagente-Chevallier, O Boufraqech, M Prenois, F Courtin, F Caillou, B Talbot, M Dardalhon, M Al Ghuzlan, A Bidart, J-M Schlumberger, M Dupuy, C Oncogene Original Article Activated Ras oncogene induces DNA-damage response by triggering reactive oxygen species (ROS) production and this is critical for oncogene-induced senescence. Until now, little connections between oncogene expression, ROS-generating NADPH oxidases and DNA-damage response have emerged from different studies. Here we report that H-RasV12 positively regulates the NADPH oxidase system NOX4-p22(phox) that produces H(2)O(2). Knocking down the NADPH oxidase with small interference RNA decreases H-RasV12-induced DNA-damage response detected by γ-H2A.X foci analysis. Using HyPer, a specific probe for H(2)O(2), we detected an increase in H(2)O(2) in the nucleus correlated with NOX4-p22(phox) perinuclear localization. DNA damage response can be caused not only by H-RasV12-driven accumulation of ROS but also by a replicative stress due to a sustained oncogenic signal. Interestingly, NOX4 downregulation by siRNA abrogated H-RasV12 regulation of CDC6 expression, an essential regulator of DNA replication. Moreover, senescence markers, such as senescence-associated heterochromatin foci, PML bodies, HP1β foci and p21 expression, induced under H-RasV12 activation were decreased with NOX4 inactivation. Taken together, our data indicate that NADPH oxidase NOX4 is a critical mediator in oncogenic H-RasV12-induced DNA-damage response and subsequent senescence. Nature Publishing Group 2012-03-01 2011-08-15 /pmc/articles/PMC3307059/ /pubmed/21841825 http://dx.doi.org/10.1038/onc.2011.327 Text en Copyright © 2012 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ |
spellingShingle | Original Article Weyemi, U Lagente-Chevallier, O Boufraqech, M Prenois, F Courtin, F Caillou, B Talbot, M Dardalhon, M Al Ghuzlan, A Bidart, J-M Schlumberger, M Dupuy, C ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence |
title | ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence |
title_full | ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence |
title_fullStr | ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence |
title_full_unstemmed | ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence |
title_short | ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence |
title_sort | ros-generating nadph oxidase nox4 is a critical mediator in oncogenic h-ras-induced dna damage and subsequent senescence |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307059/ https://www.ncbi.nlm.nih.gov/pubmed/21841825 http://dx.doi.org/10.1038/onc.2011.327 |
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