Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/20418
Título
PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation
Autor(es)
Fecha de publicación
2017-03-16
Cita
Gupta A, Anjomani-Virmouni S, Koundouros N, Dimitriadi M, Choo-Wing R, Valle A, et al. PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation. Mol Cell. 2017 Mar 16;65(6):999-1013.e7.
Idioma
Inglés
Tipo de documento
research article
Resumen
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.
MESH
Dose-Response Relationship, Drug | Enzyme Activation | Cell Movement | Humans | Ubiquitin-Protein Ligases | TOR Serine-Threonine Kinases | MCF-7 Cells | Protein Processing, Post-Translational | Cell Survival | Time Factors | AMP-Activated Protein Kinases | Oxidation-Reduction | Proto-Oncogene Proteins c-akt | Mice, Inbred NOD | Signal Transduction | Mice, Knockout | PTEN Phosphohydrolase | Gene Expression Regulation, Neoplastic | Tumor Burden | Oxidative Stress | Energy Metabolism | Transfection | HEK293 Cells | HCT116 Cells | Nitric Oxide | Antineoplastic Agents | Protein Kinase Inhibitors | Cell Proliferation | Neoplasms | Gene Expression Profiling | Nitric Oxide Synthase Type III | Animals | Ubiquitination | Phosphatidylinositol 3-Kinase | Mice, SCID | RNA Interference
DECS
Ubiquitina-Proteína Ligasas | Ratones SCID | Serina-Treonina Quinasas TOR | Células MCF-7 | Supervivencia Celular | Fosfatidilinositol 3-Quinasa | Ubiquitinación | Antineoplásicos | Metabolismo Energético | Neoplasias | Interferencia de ARN | Óxido Nítrico | Óxido Nítrico Sintasa de Tipo III | Perfilación de la Expresión Génica | Transducción de Señal | Animales | Regulación Neoplásica de la Expresión Génica | Ratones Noqueados | Células HCT116 | Proliferación Celular | Ratones Endogámicos NOD | Inhibidores de Proteínas Quinasas | Células HEK293 | Factores de Tiempo | Carga Tumoral | Movimiento Celular | Relación Dosis-Respuesta a Droga | Activación Enzimática | Humanos | Proteínas Quinasas Activadas por AMP | Procesamiento Proteico-Postraduccional | Estrés Oxidativo | Fosfohidrolasa PTEN | Transfección | Oxidación-Reducción | Proteínas Proto-Oncogénicas c-akt
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DOI
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