Differential Function of the Prolyl Hydroxylases PHD1, PHD2, and PHD3 in the Regulation of Hypoxia-inducible Factor
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Hypoxia-inducible factor (HIF) is a transcriptional regulator that plays a key role in many aspects of oxygen homeostasis. The heterodimeric HIF complex is regulated by proteolysis of its alpha-subunits, following oxygen-dependent hydroxylation of specific prolyl residues. Although three HIF prolyl hydroxylases, PHD1, PHD2, and PHD3, have been identified that have the potential to catalyze this reaction, the contribution of each isoform to the physiological regulation of HIF remains uncertain. Here we show using suppression by small interference RNA that each of the three PHD isoforms contributes in a non-redundant manner to the regulation of both HIF-1alpha and HIF-2alpha subunits and that the contribution of each PHD under particular culture conditions is strongly dependent on the abundance of the enzyme. Thus in different cell types, isoform-specific patterns of PHD induction by hypoxia and estrogen alter both the relative abundance of the PHDs and their relative contribution to the regulation of HIF. In addition, the PHDs manifest specificity for different prolyl hydroxylation sites within each HIF-alpha subunit, and a degree of selectively between HIF-1alpha and HIF-2alpha isoforms, indicating that differential PHD inhibition has the potential to selectively alter the characteristics of HIF activation.
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PHD enzyme abundance determines the relative activity of HIF-1α versus HIF-2α because PHDs differ in specificity for prolyl hydroxylation sites between HIFα isoforms.
“An important determinant of HIF-1α activity relative to HIF-2α activity is the abundance of specific PHD enzymes, which have differential specificities for prolyl hydroxylation sites between the HIFα isoforms (5).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [5]
Functional diversity between individual PHDs is expected because of differences in cellular localization, hypoxia-inducibility and biochemical behavior.
“functional diversity between individual PHDs is expected, because of differences in cellular localization, hypoxia-inducibility and biochemical behavior”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [242]
PHD1 and PHD3 appear to preferentially target HIF-2α in vitro and in vivo.
“Furthermore, PHD1 and PHD3 appear to preferentially target HIF-2α in vitro and in vivo”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [243]
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“Both PHD and HIF isoforms display substrate selectivity, with PHD2 functioning as the principal regulator of HIF-1 α stability and PHD3 preferentially modulating HIF-2 α [31,42,55,56].”
- Authors
- Appelhoff, R. J., Tian, Y.-M., Raval, R. R., Turley, H., Harris, A. L., Pugh, C. W., Ratcliffe, P. J., & Gleadle, J. M.
- Affiliations
- University of Oxford (GB)
- Cancer Research UK (GB)
- Corresponding author
- Gleadle, Jonathan M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-09
- Volume
- 279
- Issue
- 37
- Pages
- 38458-38465
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2016160962
- Cited by
- 1,108
- References
- 40
- Citations by year
- 2026: 31 · 2025: 40 · 2024: 60 · 2023: 59 · 2022: 53 · 2021: 48 · 2020: 55 · 2019: 45 · 2018: 54 · 2017: 47 · 2016: 62 · 2015: 46 · 2014: 52 · 2013: 61 · 2012: 48
- FWCI
- 18.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Cancer Research UK
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- prolyl hydroxylase, PHD1, PHD2, PHD3, hypoxia-inducible factor, HIF-1α, HIF-2α, hypoxia, estrogen, oxygen homeostasis
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Hypoxia, Catalysis, Cell Line, DNA-Binding Proteins, Estradiol, Gene Expression Regulation, Glutathione Transferase, Humans, Kinetics, Mice, Inbred BALB C, Nuclear Proteins, Oxygen, Plasmids, Procollagen-Proline Dioxygenase, Recombinant Fusion Proteins, Ribonucleases, RNA, RNA, Messenger, Sensitivity and Specificity, Transcription Factors, Immunoblotting, Trans-Activators, Immediate-Early Proteins, Protein Isoforms, RNA, Small Interfering, Cell Line, Tumor, Dioxygenases, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases
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