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The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1α Levels and Colorectal Cancer Cell Survival under Hypoxia

Oxygen-dependent HIF1α hydroxylation and degradation are strictly controlled by PHD2. In hypoxia, HIF1α partly escapes degradation because of low oxygen availability. Here, we show that PHD2 is phosphorylated on serine 125 (S125) by the mechanistic target of rapamycin (mTOR) downstream kinase P70S6K...

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Autores principales: Di Conza, Giusy, Trusso Cafarello, Sarah, Loroch, Stefan, Mennerich, Daniela, Deschoemaeker, Sofie, Di Matteo, Mario, Ehling, Manuel, Gevaert, Kris, Prenen, Hans, Zahedi, Rene Peiman, Sickmann, Albert, Kietzmann, Thomas, Moretti, Fabiola, Mazzone, Massimiliano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318657/
https://www.ncbi.nlm.nih.gov/pubmed/28199842
http://dx.doi.org/10.1016/j.celrep.2017.01.051
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author Di Conza, Giusy
Trusso Cafarello, Sarah
Loroch, Stefan
Mennerich, Daniela
Deschoemaeker, Sofie
Di Matteo, Mario
Ehling, Manuel
Gevaert, Kris
Prenen, Hans
Zahedi, Rene Peiman
Sickmann, Albert
Kietzmann, Thomas
Moretti, Fabiola
Mazzone, Massimiliano
author_facet Di Conza, Giusy
Trusso Cafarello, Sarah
Loroch, Stefan
Mennerich, Daniela
Deschoemaeker, Sofie
Di Matteo, Mario
Ehling, Manuel
Gevaert, Kris
Prenen, Hans
Zahedi, Rene Peiman
Sickmann, Albert
Kietzmann, Thomas
Moretti, Fabiola
Mazzone, Massimiliano
author_sort Di Conza, Giusy
collection PubMed
description Oxygen-dependent HIF1α hydroxylation and degradation are strictly controlled by PHD2. In hypoxia, HIF1α partly escapes degradation because of low oxygen availability. Here, we show that PHD2 is phosphorylated on serine 125 (S125) by the mechanistic target of rapamycin (mTOR) downstream kinase P70S6K and that this phosphorylation increases its ability to degrade HIF1α. mTOR blockade in hypoxia by REDD1 restrains P70S6K and unleashes PP2A phosphatase activity. Through its regulatory subunit B55α, PP2A directly dephosphorylates PHD2 on S125, resulting in a further reduction of PHD2 activity that ultimately boosts HIF1α accumulation. These events promote autophagy-mediated cell survival in colorectal cancer (CRC) cells. B55α knockdown blocks neoplastic growth of CRC cells in vitro and in vivo in a PHD2-dependent manner. In patients, CRC tissue expresses higher levels of REDD1, B55α, and HIF1α but has lower phospho-S125 PHD2 compared with a healthy colon. Our data disclose a mechanism of PHD2 regulation that involves the mTOR and PP2A pathways and controls tumor growth.
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spelling pubmed-53186572017-02-26 The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1α Levels and Colorectal Cancer Cell Survival under Hypoxia Di Conza, Giusy Trusso Cafarello, Sarah Loroch, Stefan Mennerich, Daniela Deschoemaeker, Sofie Di Matteo, Mario Ehling, Manuel Gevaert, Kris Prenen, Hans Zahedi, Rene Peiman Sickmann, Albert Kietzmann, Thomas Moretti, Fabiola Mazzone, Massimiliano Cell Rep Article Oxygen-dependent HIF1α hydroxylation and degradation are strictly controlled by PHD2. In hypoxia, HIF1α partly escapes degradation because of low oxygen availability. Here, we show that PHD2 is phosphorylated on serine 125 (S125) by the mechanistic target of rapamycin (mTOR) downstream kinase P70S6K and that this phosphorylation increases its ability to degrade HIF1α. mTOR blockade in hypoxia by REDD1 restrains P70S6K and unleashes PP2A phosphatase activity. Through its regulatory subunit B55α, PP2A directly dephosphorylates PHD2 on S125, resulting in a further reduction of PHD2 activity that ultimately boosts HIF1α accumulation. These events promote autophagy-mediated cell survival in colorectal cancer (CRC) cells. B55α knockdown blocks neoplastic growth of CRC cells in vitro and in vivo in a PHD2-dependent manner. In patients, CRC tissue expresses higher levels of REDD1, B55α, and HIF1α but has lower phospho-S125 PHD2 compared with a healthy colon. Our data disclose a mechanism of PHD2 regulation that involves the mTOR and PP2A pathways and controls tumor growth. Cell Press 2017-02-14 /pmc/articles/PMC5318657/ /pubmed/28199842 http://dx.doi.org/10.1016/j.celrep.2017.01.051 Text en © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Di Conza, Giusy
Trusso Cafarello, Sarah
Loroch, Stefan
Mennerich, Daniela
Deschoemaeker, Sofie
Di Matteo, Mario
Ehling, Manuel
Gevaert, Kris
Prenen, Hans
Zahedi, Rene Peiman
Sickmann, Albert
Kietzmann, Thomas
Moretti, Fabiola
Mazzone, Massimiliano
The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1α Levels and Colorectal Cancer Cell Survival under Hypoxia
title The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1α Levels and Colorectal Cancer Cell Survival under Hypoxia
title_full The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1α Levels and Colorectal Cancer Cell Survival under Hypoxia
title_fullStr The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1α Levels and Colorectal Cancer Cell Survival under Hypoxia
title_full_unstemmed The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1α Levels and Colorectal Cancer Cell Survival under Hypoxia
title_short The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1α Levels and Colorectal Cancer Cell Survival under Hypoxia
title_sort mtor and pp2a pathways regulate phd2 phosphorylation to fine-tune hif1α levels and colorectal cancer cell survival under hypoxia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318657/
https://www.ncbi.nlm.nih.gov/pubmed/28199842
http://dx.doi.org/10.1016/j.celrep.2017.01.051
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