Oxidative Dimerization of PHD2 is Responsible for its Inactivation and Contributes to Metabolic Reprogramming via HIF-1α Activation
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Lee, Gibok
Won, Hyung-Sik
Lee, Yoon-Mi
Choi, Jae-Wan
Oh, Taek-In
Jang, Jeong-Hwa
Choi, Dong-Kug
Lim, Beong-Ou
Kim, Young Jun
Park, Jong-Wan
Lim, Ji-Hong
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https://doi.org/10.1038/srep18928Metadata
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Lee, G., H. Won, Y. Lee, J. Choi, T. Oh, J. Jang, D. Choi, et al. 2016. “Oxidative Dimerization of PHD2 is Responsible for its Inactivation and Contributes to Metabolic Reprogramming via HIF-1α Activation.” Scientific Reports 6 (1): 18928. doi:10.1038/srep18928. http://dx.doi.org/10.1038/srep18928.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-rasV12 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-rasV12 signalling facilitates the accumulation of HIF-1α in the nucleus and promotes aerobic glycolysis and lactate production. Moreover, oncogenic H-rasV12 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-rasV12-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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703963/pdf/Terms of Use
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