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Oxidative Dimerization of PHD2 is Responsible for its Inactivation and Contributes to Metabolic Reprogramming via HIF-1α Activation.
Sci Rep 2016; 6:18928SR

Abstract

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-1α (HIF-1α) 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 β-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-1α under oxidative stress. Oncogenic H-ras(V12) signalling facilitates the accumulation of HIF-1α 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-1α and aerobic glycolysis in response to oxidative stress.

Authors+Show Affiliations

Department of Biomedical Chemistry, College of Biomedical &Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.Department of Biotechnology, College of Biomedical &Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.Department of Food Bioscience, College of Biomedical &Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.Department of Biotechnology, College of Biomedical &Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.Department of Biomedical Chemistry, College of Biomedical &Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.Department of Biotechnology, College of Biomedical &Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.Department of Biotechnology, College of Biomedical &Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.Department of Biomedical Chemistry, College of Biomedical &Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.Department of Biomedical Chemistry, College of Biomedical &Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.Department of Pharmacology, Seoul National University, College of Medicine, Seoul 110-799, Republic of Korea.Department of Cancer Biology, Dana-Farber Cancer Institute; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.Department of Biomedical Chemistry, College of Biomedical &Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26740011

Citation

Lee, Gibok, et al. "Oxidative Dimerization of PHD2 Is Responsible for Its Inactivation and Contributes to Metabolic Reprogramming Via HIF-1α Activation." Scientific Reports, vol. 6, 2016, p. 18928.
Lee G, Won HS, Lee YM, et al. Oxidative Dimerization of PHD2 is Responsible for its Inactivation and Contributes to Metabolic Reprogramming via HIF-1α Activation. Sci Rep. 2016;6:18928.
Lee, G., Won, H. S., Lee, Y. M., Choi, J. W., Oh, T. I., Jang, J. H., ... Lim, J. H. (2016). Oxidative Dimerization of PHD2 is Responsible for its Inactivation and Contributes to Metabolic Reprogramming via HIF-1α Activation. Scientific Reports, 6, p. 18928. doi:10.1038/srep18928.
Lee G, et al. Oxidative Dimerization of PHD2 Is Responsible for Its Inactivation and Contributes to Metabolic Reprogramming Via HIF-1α Activation. Sci Rep. 2016 Jan 7;6:18928. PubMed PMID: 26740011.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oxidative Dimerization of PHD2 is Responsible for its Inactivation and Contributes to Metabolic Reprogramming via HIF-1α Activation. AU - Lee,Gibok, AU - Won,Hyung-Sik, AU - Lee,Yoon-Mi, AU - Choi,Jae-Wan, AU - Oh,Taek-In, AU - Jang,Jeong-Hwa, AU - Choi,Dong-Kug, AU - Lim,Beong-Ou, AU - Kim,Young Jun, AU - Park,Jong-Wan, AU - Puigserver,Pere, AU - Lim,Ji-Hong, Y1 - 2016/01/07/ PY - 2015/08/18/received PY - 2015/11/30/accepted PY - 2016/1/8/entrez PY - 2016/1/8/pubmed PY - 2016/12/15/medline SP - 18928 EP - 18928 JF - Scientific reports JO - Sci Rep VL - 6 N2 - 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-1α (HIF-1α) 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 β-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-1α under oxidative stress. Oncogenic H-ras(V12) signalling facilitates the accumulation of HIF-1α 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-1α and aerobic glycolysis in response to oxidative stress. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/26740011/Oxidative_Dimerization_of_PHD2_is_Responsible_for_its_Inactivation_and_Contributes_to_Metabolic_Reprogramming_via_HIF_1α_Activation_ L2 - http://dx.doi.org/10.1038/srep18928 DB - PRIME DP - Unbound Medicine ER -