dc.contributor.author | Gupta, A | |
dc.contributor.author | Anjomani-Virmouni, S | |
dc.contributor.author | Koundouros, N | |
dc.contributor.author | Dimitriadi, M | |
dc.contributor.author | Choo-Wing, R | |
dc.contributor.author | Valle, A | |
dc.contributor.author | Zheng, Y | |
dc.contributor.author | Chiu, Y-H | |
dc.contributor.author | Agnihotri, S | |
dc.contributor.author | Zadeh, G | |
dc.contributor.author | Asara, JM | |
dc.contributor.author | Anastasiou, D | |
dc.contributor.author | Arends, MJ | |
dc.contributor.author | Cantley, LC | |
dc.contributor.author | Poulogiannis, G | |
dc.date.accessioned | 2017-04-03T09:53:23Z | |
dc.date.issued | 2017-03-16 | |
dc.identifier.citation | Molecular cell, 2017, 65 (6), pp. 999 - 1013.e7 | |
dc.identifier.issn | 1097-2765 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/544 | |
dc.identifier.eissn | 1097-4164 | |
dc.identifier.doi | 10.1016/j.molcel.2017.02.019 | |
dc.description.abstract | 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. | |
dc.format | Print | |
dc.format.extent | 999 - 1013.e7 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | CELL PRESS | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | HCT116 Cells | |
dc.subject | Animals | |
dc.subject | Mice, Inbred NOD | |
dc.subject | Mice, Knockout | |
dc.subject | Humans | |
dc.subject | Mice, SCID | |
dc.subject | Neoplasms | |
dc.subject | Nitric Oxide | |
dc.subject | Ubiquitin-Protein Ligases | |
dc.subject | Antineoplastic Agents | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Tumor Burden | |
dc.subject | Gene Expression Profiling | |
dc.subject | Transfection | |
dc.subject | Signal Transduction | |
dc.subject | Cell Proliferation | |
dc.subject | Cell Movement | |
dc.subject | Cell Survival | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | RNA Interference | |
dc.subject | Protein Processing, Post-Translational | |
dc.subject | Enzyme Activation | |
dc.subject | Energy Metabolism | |
dc.subject | Oxidation-Reduction | |
dc.subject | Oxidative Stress | |
dc.subject | Dose-Response Relationship, Drug | |
dc.subject | Time Factors | |
dc.subject | Proto-Oncogene Proteins c-akt | |
dc.subject | PTEN Phosphohydrolase | |
dc.subject | Nitric Oxide Synthase Type III | |
dc.subject | Ubiquitination | |
dc.subject | AMP-Activated Protein Kinases | |
dc.subject | HEK293 Cells | |
dc.subject | Phosphatidylinositol 3-Kinase | |
dc.subject | TOR Serine-Threonine Kinases | |
dc.subject | MCF-7 Cells | |
dc.subject | Phosphoinositide-3 Kinase Inhibitors | |
dc.title | PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-02-17 | |
rioxxterms.versionofrecord | 10.1016/j.molcel.2017.02.019 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2017-03 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Molecular cell | |
pubs.issue | 6 | |
pubs.notes | 12 months | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Signalling & Cancer Metabolism | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Signalling & Cancer Metabolism | |
pubs.publication-status | Published | |
pubs.volume | 65 | |
pubs.embargo.terms | 12 months | |
icr.researchteam | Signalling & Cancer Metabolism | |
dc.contributor.icrauthor | Koundouros, Nikolaos | |
dc.contributor.icrauthor | Poulogiannis, Georgios | |