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Mitochondrial AKAP1 supports mTOR pathway and tumor growth

Mitochondria are the powerhouses of energy production and the sites where metabolic pathway and survival signals integrate and focus, promoting adaptive responses to hormone stimulation and nutrient availability. Increasing evidence suggests that mitochondrial bioenergetics, metabolism and signaling...

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Autores principales: Rinaldi, Laura, Sepe, Maria, Delle Donne, Rossella, Conte, Kristel, Arcella, Antonietta, Borzacchiello, Domenica, Amente, Stefano, De Vita, Fernanda, Porpora, Monia, Garbi, Corrado, Oliva, Maria A, Procaccini, Claudio, Faicchia, Deriggio, Matarese, Giuseppe, Zito Marino, Federica, Rocco, Gaetano, Pignatiello, Sara, Franco, Renato, Insabato, Luigi, Majello, Barbara, Feliciello, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520900/
https://www.ncbi.nlm.nih.gov/pubmed/28569781
http://dx.doi.org/10.1038/cddis.2017.241
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author Rinaldi, Laura
Sepe, Maria
Delle Donne, Rossella
Conte, Kristel
Arcella, Antonietta
Borzacchiello, Domenica
Amente, Stefano
De Vita, Fernanda
Porpora, Monia
Garbi, Corrado
Oliva, Maria A
Procaccini, Claudio
Faicchia, Deriggio
Matarese, Giuseppe
Zito Marino, Federica
Rocco, Gaetano
Pignatiello, Sara
Franco, Renato
Insabato, Luigi
Majello, Barbara
Feliciello, Antonio
author_facet Rinaldi, Laura
Sepe, Maria
Delle Donne, Rossella
Conte, Kristel
Arcella, Antonietta
Borzacchiello, Domenica
Amente, Stefano
De Vita, Fernanda
Porpora, Monia
Garbi, Corrado
Oliva, Maria A
Procaccini, Claudio
Faicchia, Deriggio
Matarese, Giuseppe
Zito Marino, Federica
Rocco, Gaetano
Pignatiello, Sara
Franco, Renato
Insabato, Luigi
Majello, Barbara
Feliciello, Antonio
author_sort Rinaldi, Laura
collection PubMed
description Mitochondria are the powerhouses of energy production and the sites where metabolic pathway and survival signals integrate and focus, promoting adaptive responses to hormone stimulation and nutrient availability. Increasing evidence suggests that mitochondrial bioenergetics, metabolism and signaling are linked to tumorigenesis. AKAP1 scaffolding protein integrates cAMP and src signaling on mitochondria, regulating organelle biogenesis, oxidative metabolism and cell survival. Here, we provide evidence that AKAP1 is a transcriptional target of Myc and supports the growth of cancer cells. We identify Sestrin2, a leucine sensor and inhibitor of the mammalian target of rapamycin (mTOR), as a novel component of the complex assembled by AKAP1 on mitochondria. Downregulation of AKAP1 impaired mTOR pathway and inhibited glioblastoma growth. Both effects were reversed by concomitant depletion of AKAP1 and sestrin2. High levels of AKAP1 were found in a wide variety of high-grade cancer tissues. In lung cancer, AKAP1 expression correlates with high levels of Myc, mTOR phosphorylation and reduced patient survival. Collectively, these data disclose a previously unrecognized role of AKAP1 in mTOR pathway regulation and cancer growth. AKAP1/mTOR signal integration on mitochondria may provide a new target for cancer therapy.
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spelling pubmed-55209002017-07-27 Mitochondrial AKAP1 supports mTOR pathway and tumor growth Rinaldi, Laura Sepe, Maria Delle Donne, Rossella Conte, Kristel Arcella, Antonietta Borzacchiello, Domenica Amente, Stefano De Vita, Fernanda Porpora, Monia Garbi, Corrado Oliva, Maria A Procaccini, Claudio Faicchia, Deriggio Matarese, Giuseppe Zito Marino, Federica Rocco, Gaetano Pignatiello, Sara Franco, Renato Insabato, Luigi Majello, Barbara Feliciello, Antonio Cell Death Dis Original Article Mitochondria are the powerhouses of energy production and the sites where metabolic pathway and survival signals integrate and focus, promoting adaptive responses to hormone stimulation and nutrient availability. Increasing evidence suggests that mitochondrial bioenergetics, metabolism and signaling are linked to tumorigenesis. AKAP1 scaffolding protein integrates cAMP and src signaling on mitochondria, regulating organelle biogenesis, oxidative metabolism and cell survival. Here, we provide evidence that AKAP1 is a transcriptional target of Myc and supports the growth of cancer cells. We identify Sestrin2, a leucine sensor and inhibitor of the mammalian target of rapamycin (mTOR), as a novel component of the complex assembled by AKAP1 on mitochondria. Downregulation of AKAP1 impaired mTOR pathway and inhibited glioblastoma growth. Both effects were reversed by concomitant depletion of AKAP1 and sestrin2. High levels of AKAP1 were found in a wide variety of high-grade cancer tissues. In lung cancer, AKAP1 expression correlates with high levels of Myc, mTOR phosphorylation and reduced patient survival. Collectively, these data disclose a previously unrecognized role of AKAP1 in mTOR pathway regulation and cancer growth. AKAP1/mTOR signal integration on mitochondria may provide a new target for cancer therapy. Nature Publishing Group 2017-06 2017-06-01 /pmc/articles/PMC5520900/ /pubmed/28569781 http://dx.doi.org/10.1038/cddis.2017.241 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Rinaldi, Laura
Sepe, Maria
Delle Donne, Rossella
Conte, Kristel
Arcella, Antonietta
Borzacchiello, Domenica
Amente, Stefano
De Vita, Fernanda
Porpora, Monia
Garbi, Corrado
Oliva, Maria A
Procaccini, Claudio
Faicchia, Deriggio
Matarese, Giuseppe
Zito Marino, Federica
Rocco, Gaetano
Pignatiello, Sara
Franco, Renato
Insabato, Luigi
Majello, Barbara
Feliciello, Antonio
Mitochondrial AKAP1 supports mTOR pathway and tumor growth
title Mitochondrial AKAP1 supports mTOR pathway and tumor growth
title_full Mitochondrial AKAP1 supports mTOR pathway and tumor growth
title_fullStr Mitochondrial AKAP1 supports mTOR pathway and tumor growth
title_full_unstemmed Mitochondrial AKAP1 supports mTOR pathway and tumor growth
title_short Mitochondrial AKAP1 supports mTOR pathway and tumor growth
title_sort mitochondrial akap1 supports mtor pathway and tumor growth
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520900/
https://www.ncbi.nlm.nih.gov/pubmed/28569781
http://dx.doi.org/10.1038/cddis.2017.241
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