PMID- 26740011
OWN - NLM
STAT- MEDLINE
DCOM- 20161213
LR  - 20181113
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 6
DP  - 2016 Jan 7
TI  - Oxidative Dimerization of PHD2 is Responsible for its Inactivation and 
      Contributes to Metabolic Reprogramming via HIF-1alpha Activation.
PG  - 18928
LID - 10.1038/srep18928 [doi]
LID - 18928
AB  - Prolyl hydroxylase domain protein 2 (PHD2) belongs to an evolutionarily conserved 
      superfamily of 2-oxoglutarate and Fe(II)-dependent dioxygenases that mediates 
      homeostatic responses to oxygen deprivation by mediating hypoxia-inducible 
      factor-1alpha (HIF-1alpha) hydroxylation and degradation. Although oxidative stress 
      contributes to the inactivation of PHD2, the precise molecular mechanism of PHD2 
      inactivation independent of the levels of co-factors is not understood. Here, we 
      identified disulfide bond-mediated PHD2 homo-dimer formation in response to 
      oxidative stress caused by oxidizing agents and oncogenic H-ras(V12) signalling. 
      Cysteine residues in the double-stranded beta-helix fold that constitutes the 
      catalytic site of PHD isoforms appeared responsible for the oxidative 
      dimerization. Furthermore, we demonstrated that disulfide bond-mediated PHD2 
      dimerization is associated with the stabilization and activation of HIF-1alpha under 
      oxidative stress. Oncogenic H-ras(V12) signalling facilitates the accumulation of 
      HIF-1alpha in the nucleus and promotes aerobic glycolysis and lactate production. 
      Moreover, oncogenic H-ras(V12) does not trigger aerobic glycolysis in 
      antioxidant-treated or PHD2 knocked-down cells, suggesting the participation of 
      the ROS-mediated PHD2 inactivation in the oncogenic H-ras(V12)-mediated metabolic 
      reprogramming. We provide here a better understanding of the mechanism by which 
      disulfide bond-mediated PHD2 dimerization and inactivation result in the 
      activation of HIF-1alpha and aerobic glycolysis in response to oxidative stress.
FAU - Lee, Gibok
AU  - Lee G
AD  - Department of Biomedical Chemistry, College of Biomedical &Health Science, Konkuk 
      University, Chungju 380-701, Chungbuk, Republic of Korea.
FAU - Won, Hyung-Sik
AU  - Won HS
AD  - Department of Biotechnology, College of Biomedical &Health Science, Konkuk 
      University, Chungju 380-701, Chungbuk, Republic of Korea.
FAU - Lee, Yoon-Mi
AU  - Lee YM
AD  - Department of Food Bioscience, College of Biomedical &Health Science, Konkuk 
      University, Chungju 380-701, Chungbuk, Republic of Korea.
FAU - Choi, Jae-Wan
AU  - Choi JW
AD  - Department of Biotechnology, College of Biomedical &Health Science, Konkuk 
      University, Chungju 380-701, Chungbuk, Republic of Korea.
FAU - Oh, Taek-In
AU  - Oh TI
AD  - Department of Biomedical Chemistry, College of Biomedical &Health Science, Konkuk 
      University, Chungju 380-701, Chungbuk, Republic of Korea.
FAU - Jang, Jeong-Hwa
AU  - Jang JH
AD  - Department of Biotechnology, College of Biomedical &Health Science, Konkuk 
      University, Chungju 380-701, Chungbuk, Republic of Korea.
FAU - Choi, Dong-Kug
AU  - Choi DK
AD  - Department of Biotechnology, College of Biomedical &Health Science, Konkuk 
      University, Chungju 380-701, Chungbuk, Republic of Korea.
FAU - Lim, Beong-Ou
AU  - Lim BO
AD  - Department of Biomedical Chemistry, College of Biomedical &Health Science, Konkuk 
      University, Chungju 380-701, Chungbuk, Republic of Korea.
FAU - Kim, Young Jun
AU  - Kim YJ
AD  - Department of Biomedical Chemistry, College of Biomedical &Health Science, Konkuk 
      University, Chungju 380-701, Chungbuk, Republic of Korea.
FAU - Park, Jong-Wan
AU  - Park JW
AD  - Department of Pharmacology, Seoul National University, College of Medicine, Seoul 
      110-799, Republic of Korea.
FAU - Puigserver, Pere
AU  - Puigserver P
AD  - Department of Cancer Biology, Dana-Farber Cancer Institute; Department of Cell 
      Biology, Harvard Medical School, Boston, Massachusetts, USA.
FAU - Lim, Ji-Hong
AU  - Lim JH
AD  - Department of Biomedical Chemistry, College of Biomedical &Health Science, Konkuk 
      University, Chungju 380-701, Chungbuk, Republic of Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160107
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Reactive Oxygen Species)
RN  - 48TCX9A1VT (Cystine)
RN  - EC 1.14.11.2 (EGLN1 protein, human)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
RN  - EC 3.6.5.2 (HRAS protein, human)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
SB  - IM
MH  - Amino Acid Sequence
MH  - Cell Line, Tumor
MH  - Cystine/metabolism
MH  - Glycolysis
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases/*metabolism
MH  - Oxidation-Reduction
MH  - *Oxidative Stress
MH  - Protein Multimerization
MH  - Protein Stability
MH  - Proto-Oncogene Proteins p21(ras)/genetics/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction
PMC - PMC4703963
EDAT- 2016/01/08 06:00
MHDA- 2016/12/15 06:00
PMCR- 2016/01/07
CRDT- 2016/01/08 06:00
PHST- 2015/08/18 00:00 [received]
PHST- 2015/11/30 00:00 [accepted]
PHST- 2016/01/08 06:00 [entrez]
PHST- 2016/01/08 06:00 [pubmed]
PHST- 2016/12/15 06:00 [medline]
PHST- 2016/01/07 00:00 [pmc-release]
AID - srep18928 [pii]
AID - 10.1038/srep18928 [doi]
PST - epublish
SO  - Sci Rep. 2016 Jan 7;6:18928. doi: 10.1038/srep18928.