PMID- 27325674
OWN - NLM
STAT- MEDLINE
DCOM- 20170529
LR  - 20181113
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 36
IP  - 18
DP  - 2016 Sep 15
TI  - The Zinc Finger of Prolyl Hydroxylase Domain Protein 2 Is Essential for Efficient 
      Hydroxylation of Hypoxia-Inducible Factor alpha.
PG  - 2328-43
LID - 10.1128/MCB.00090-16 [doi]
AB  - Prolyl hydroxylase domain protein 2 (PHD2) (also known as EGLN1) is a key oxygen 
      sensor in mammals that posttranslationally modifies hypoxia-inducible factor alpha 
      (HIF-alpha) and targets it for degradation. In addition to its catalytic domain, PHD2 
      contains an evolutionarily conserved zinc finger domain, which we have previously 
      proposed recruits PHD2 to the HSP90 pathway to promote HIF-alpha hydroxylation. Here, 
      we provide evidence that this recruitment is critical both in vitro and in vivo 
      We show that in vitro, the zinc finger can function as an autonomous recruitment 
      domain to facilitate interaction with HIF-alpha. In vivo, ablation of zinc finger 
      function by a C36S/C42S Egln1 knock-in mutation results in upregulation of the 
      erythropoietin gene, erythrocytosis, and augmented hypoxic ventilatory response, 
      all hallmarks of Egln1 loss of function and HIF stabilization. Hence, the zinc 
      finger ordinarily performs a critical positive regulatory function. Intriguingly, 
      the function of this zinc finger is impaired in high-altitude-adapted Tibetans, 
      suggesting that their adaptation to high altitude may, in part, be due to a 
      loss-of-function EGLN1 allele. Thus, these findings have important implications 
      for understanding both the molecular mechanism of the hypoxic response and human 
      adaptation to high altitude.
CI  - Copyright (c) 2016, American Society for Microbiology. All Rights Reserved.
FAU - Arsenault, Patrick R
AU  - Arsenault PR
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Song, Daisheng
AU  - Song D
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Chung, Yu Jin
AU  - Chung YJ
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Khurana, Tejvir S
AU  - Khurana TS
AD  - Department of Physiology and Pennsylvania Muscle Institute, Perelman School of 
      Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Lee, Frank S
AU  - Lee FS
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania, USA 
      franklee@mail.med.upenn.edu.
LA  - eng
SI  - PDB/2ODD
GR  - R01 DK104796/DK/NIDDK NIH HHS/United States
GR  - T32 DK007780/DK/NIDDK NIH HHS/United States
GR  - P30 DK050306/DK/NIDDK NIH HHS/United States
GR  - R33 HL120751/HL/NHLBI NIH HHS/United States
GR  - R21 HL120751/HL/NHLBI NIH HHS/United States
GR  - R01 CA153347/CA/NCI NIH HHS/United States
GR  - P30 CA016520/CA/NCI NIH HHS/United States
GR  - P30 DK019525/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20160826
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
SB  - IM
MH  - Adaptation, Physiological
MH  - Animals
MH  - Catalytic Domain
MH  - Cells, Cultured
MH  - Gene Knockout Techniques
MH  - HSP90 Heat-Shock Proteins/*metabolism
MH  - Humans
MH  - Hydroxylation
MH  - Hypoxia/*metabolism
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases/*chemistry/genetics/*metabolism
MH  - Mice
MH  - Polycythemia/*genetics
MH  - Signal Transduction
MH  - Tibet
MH  - Transcription Factors/*metabolism
MH  - Zinc Fingers
PMC - PMC5007793
EDAT- 2016/06/22 06:00
MHDA- 2017/05/30 06:00
PMCR- 2017/02/26
CRDT- 2016/06/22 06:00
PHST- 2016/02/10 00:00 [received]
PHST- 2016/06/12 00:00 [accepted]
PHST- 2017/02/26 00:00 [pmc-release]
PHST- 2016/06/22 06:00 [entrez]
PHST- 2016/06/22 06:00 [pubmed]
PHST- 2017/05/30 06:00 [medline]
AID - MCB.00090-16 [pii]
AID - 00090-16 [pii]
AID - 10.1128/MCB.00090-16 [doi]
PST - epublish
SO  - Mol Cell Biol. 2016 Aug 26;36(18):2328-43. doi: 10.1128/MCB.00090-16. Print 2016 
      Sep 15.