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The mTOR and PP2A pathways regulate PHD2 phosphorylation to fine-tune HIF1α levels and colorectal cancer cell survival under hypoxia

(2017) CELL REPORTS. 18(7). p.1699-1712
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Abstract
Oxygen-dependent HIF1 alpha hydroxylation and degradation are strictly controlled by PHD2. In hypoxia, HIF1 alpha 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 HIF1 alpha. mTOR blockade in hypoxia by REDD1 restrains P70S6K and unleashes PP2A phosphatase activity. Through its regulatory subunit B55 alpha, PP2A directly dephosphorylates PHD2 on S125, resulting in a further reduction of PHD2 activity that ultimately boosts HIF1a accumulation. These events promote autophagy- mediated cell survival in colorectal cancer (CRC) cells. B55 alpha 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, B55 alpha, and HIF1 alpha 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.
Keywords
PROLYL HYDROXYLASES, INDUCIBLE FACTOR, MAMMALIAN TARGET, AUTOPHAGY, HIF, INHIBITION, EXPRESSION, REDD1, DEGRADATION, PROTEIN

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Chicago
Di Conza, Giusy, Sarah Trusso Cafarello, Stefan Loroch, Daniela Mennerich, Sofie Deschoemaeker, Mario Di Matteo, Manuel Ehling, et al. 2017. “The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-tune HIF1α Levels and Colorectal Cancer Cell Survival Under Hypoxia.” Cell Reports 18 (7): 1699–1712.
APA
Di Conza, G., Trusso Cafarello, S., Loroch, S., Mennerich, D., Deschoemaeker, S., Di Matteo, M., Ehling, M., et al. (2017). The mTOR and PP2A pathways regulate PHD2 phosphorylation to fine-tune HIF1α levels and colorectal cancer cell survival under hypoxia. CELL REPORTS, 18(7), 1699–1712.
Vancouver
1.
Di Conza G, Trusso Cafarello S, Loroch S, Mennerich D, Deschoemaeker S, Di Matteo M, et al. The mTOR and PP2A pathways regulate PHD2 phosphorylation to fine-tune HIF1α levels and colorectal cancer cell survival under hypoxia. CELL REPORTS. 2017;18(7):1699–712.
MLA
Di Conza, Giusy, Sarah Trusso Cafarello, Stefan Loroch, et al. “The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-tune HIF1α Levels and Colorectal Cancer Cell Survival Under Hypoxia.” CELL REPORTS 18.7 (2017): 1699–1712. Print.
@article{8512456,
  abstract     = {Oxygen-dependent HIF1 alpha hydroxylation and degradation are strictly controlled by PHD2. In hypoxia, HIF1 alpha 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 HIF1 alpha. mTOR blockade in hypoxia by REDD1 restrains P70S6K and unleashes PP2A phosphatase activity. Through its regulatory subunit B55 alpha, PP2A directly dephosphorylates PHD2 on S125, resulting in a further reduction of PHD2 activity that ultimately boosts HIF1a accumulation. These events promote autophagy- mediated cell survival in colorectal cancer (CRC) cells. B55 alpha 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, B55 alpha, and HIF1 alpha 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.},
  author       = {Di Conza, Giusy and Trusso Cafarello, Sarah and Loroch, Stefan and Mennerich, Daniela and Deschoemaeker, Sofie and Di Matteo, Mario and Ehling, Manuel and Gevaert, Kris and Prenen, Hans and Zahedi, Rene Peiman and Sickmann, Albert and Kietzmann, Thomas and Moretti, Fabiola and Mazzone, Massimiliano},
  issn         = {2211-1247},
  journal      = {CELL REPORTS},
  keyword      = {PROLYL HYDROXYLASES,INDUCIBLE FACTOR,MAMMALIAN TARGET,AUTOPHAGY,HIF,INHIBITION,EXPRESSION,REDD1,DEGRADATION,PROTEIN},
  language     = {eng},
  number       = {7},
  pages        = {1699--1712},
  title        = {The mTOR and PP2A pathways regulate PHD2 phosphorylation to fine-tune HIF1\ensuremath{\alpha} levels and colorectal cancer cell survival under hypoxia},
  url          = {http://dx.doi.org/10.1016/j.celrep.2017.01.051},
  volume       = {18},
  year         = {2017},
}

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