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PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation
PARK2 is a gene implicated in disease states with opposing responses in cell fate determination, yet its contribution in pro-survival signaling is largely unknown. Here we show that PARK2 is altered in over a third of all human cancers, and its depletion results in enhanced phosphatidylinositol 3-ki...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426642/ https://www.ncbi.nlm.nih.gov/pubmed/28306514 http://dx.doi.org/10.1016/j.molcel.2017.02.019 |
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author | Gupta, Amit Anjomani-Virmouni, Sara Koundouros, Nikos Dimitriadi, Maria Choo-Wing, Rayman Valle, Adamo Zheng, Yuxiang Chiu, Yu-Hsin Agnihotri, Sameer Zadeh, Gelareh Asara, John M. Anastasiou, Dimitrios Arends, Mark J. Cantley, Lewis C. Poulogiannis, George |
author_facet | Gupta, Amit Anjomani-Virmouni, Sara Koundouros, Nikos Dimitriadi, Maria Choo-Wing, Rayman Valle, Adamo Zheng, Yuxiang Chiu, Yu-Hsin Agnihotri, Sameer Zadeh, Gelareh Asara, John M. Anastasiou, Dimitrios Arends, Mark J. Cantley, Lewis C. Poulogiannis, George |
author_sort | Gupta, Amit |
collection | PubMed |
description | PARK2 is a gene implicated in disease states with opposing responses in cell fate determination, yet its contribution in pro-survival signaling is largely unknown. Here we show that PARK2 is altered in over a third of all human cancers, and its depletion results in enhanced phosphatidylinositol 3-kinase/Akt (PI3K/Akt) activation and increased vulnerability to PI3K/Akt/mTOR inhibitors. PARK2 depletion contributes to AMPK-mediated activation of endothelial nitric oxide synthase (eNOS), enhanced levels of reactive oxygen species, and a concomitant increase in oxidized nitric oxide levels, thereby promoting the inhibition of PTEN by S-nitrosylation and ubiquitination. Notably, AMPK activation alone is sufficient to induce PTEN S-nitrosylation in the absence of PARK2 depletion. Park2 loss and Pten loss also display striking cooperativity to promote tumorigenesis in vivo. Together, our findings reveal an important missing mechanism that might account for PTEN suppression in PARK2-deficient tumors, and they highlight the importance of PTEN S-nitrosylation in supporting cell survival and proliferation under conditions of energy deprivation. |
format | Online Article Text |
id | pubmed-5426642 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-54266422018-03-16 PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation Gupta, Amit Anjomani-Virmouni, Sara Koundouros, Nikos Dimitriadi, Maria Choo-Wing, Rayman Valle, Adamo Zheng, Yuxiang Chiu, Yu-Hsin Agnihotri, Sameer Zadeh, Gelareh Asara, John M. Anastasiou, Dimitrios Arends, Mark J. Cantley, Lewis C. Poulogiannis, George Mol Cell Article PARK2 is a gene implicated in disease states with opposing responses in cell fate determination, yet its contribution in pro-survival signaling is largely unknown. Here we show that PARK2 is altered in over a third of all human cancers, and its depletion results in enhanced phosphatidylinositol 3-kinase/Akt (PI3K/Akt) activation and increased vulnerability to PI3K/Akt/mTOR inhibitors. PARK2 depletion contributes to AMPK-mediated activation of endothelial nitric oxide synthase (eNOS), enhanced levels of reactive oxygen species, and a concomitant increase in oxidized nitric oxide levels, thereby promoting the inhibition of PTEN by S-nitrosylation and ubiquitination. Notably, AMPK activation alone is sufficient to induce PTEN S-nitrosylation in the absence of PARK2 depletion. Park2 loss and Pten loss also display striking cooperativity to promote tumorigenesis in vivo. Together, our findings reveal an important missing mechanism that might account for PTEN suppression in PARK2-deficient tumors, and they highlight the importance of PTEN S-nitrosylation in supporting cell survival and proliferation under conditions of energy deprivation. Cell Press 2017-03-16 /pmc/articles/PMC5426642/ /pubmed/28306514 http://dx.doi.org/10.1016/j.molcel.2017.02.019 Text en © 2017 The Authors. Published by Elsevier Inc. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Gupta, Amit Anjomani-Virmouni, Sara Koundouros, Nikos Dimitriadi, Maria Choo-Wing, Rayman Valle, Adamo Zheng, Yuxiang Chiu, Yu-Hsin Agnihotri, Sameer Zadeh, Gelareh Asara, John M. Anastasiou, Dimitrios Arends, Mark J. Cantley, Lewis C. Poulogiannis, George PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation |
title | PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation |
title_full | PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation |
title_fullStr | PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation |
title_full_unstemmed | PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation |
title_short | PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation |
title_sort | park2 depletion connects energy and oxidative stress to pi3k/akt activation via pten s-nitrosylation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426642/ https://www.ncbi.nlm.nih.gov/pubmed/28306514 http://dx.doi.org/10.1016/j.molcel.2017.02.019 |
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