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Title: The mTOR and PP2A pathways regulate PHD2 phosphorylation to Fine-Tune HIF1α levels and colorectal cancer cell survival under hypoxia
Authors: Di Conza, GiusyCafarello, Sarah TrussoLoroch, StefanMennerich, DanielaDeschoemaeker, SofieDi Matteo, MarioEhling, ManuelGevaert, KrisPrenen, HansZahedi, Rene PeimanSickmann, AlbertKietzmann, ThomasMoretti, FabiolaMazzone, Massimiliano
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Issue Date: 2017
Published in: Cell Reports, Volume 18, Issue 7, Page 1699-1712
Publisher: Amsterdam : Elsevier
Abstract: 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.
Keywords: hypoxia inducible factor 1; alphamammalian target of rapamycinphosphatase; PP2A protein; REDD1 proteinserine; unclassified drug; EGLN1 protein; human; HIF1A protein; human; hypoxia inducible factor 1alpha; hypoxia inducible factor proline dioxygenase; MTOR protein; human; phosphoprotein phosphatase 2; S6 kinase; target of rapamycin kinase
DDC: 570
License: CC BY-NC-ND 4.0 Unported
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