Hypoxia-inducible factor prolyl 4-hydroxylases: common and specific roles
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Johanna Myllyharju
Johanna Myllyharju is Professor of Molecular Biology and the Scientific Director of Biocenter Oulu, University of Oulu. Her research focuses on the key enzymes involved in the regulation of collagen synthesis and hypoxia response. She is a Member of the Academy of Finland Health Sciences Council and a Member of the Management Committee of the EU COST Action TD0901 HypoxiaNet.
and
Peppi Koivunen
Peppi Koivunen is Professor of Medical Biochemistry in the University of Oulu, Finland. Her research focus is 2-oxoglutaratedependent dioxy genases, such as the HIF prolyl 4-hydroxylases, the HIF asparaginyl hydroxylase FIH and a novel transmembrane prolyl 4-hydroxylase, P4H-TM. Koivunen also studies the role of 2-oxoglutarate analogues in cancer, erythropoiesis, ischemia and metabolism.
Abstract
Hypoxia-inducible transcription factor (HIF), an αβ dimer, is the key inducer of hypoxia-responsive genes that operate both during normal development and pathological processes in association with decreased oxygen availability. The products of HIF target genes function in, e.g., hematopoiesis, angiogenesis, iron transport, glucose utilization, resistance to oxidative stress, cell proliferation, survival and apoptosis, extracellular matrix homeostasis, and tumorigenesis and metastasis. HIF is accumulated in hypoxia, whereas it is rapidly degraded in normoxic cells. The oxygen-sensing mechanism behind this phenomenon is provided by HIF prolyl 4-hydroxylases (HIF-P4Hs, commonly known as PHDs and EglNs) that require oxygen in their reaction. In normoxia, two prolines in the oxygen-dependent degradation domain of the HIFα subunit become hydroxylated by the HIF-P4Hs. The 4-hydroxyproline residues formed serve as recognition sites for the von Hippel-Lindau E3 ubiquitin ligase complex and result in subsequent ubiquitination and instant proteasomal degradation of HIFα in normoxia. The HIF-P4H reaction is inhibited in hypoxia. HIFα evades degradation and forms a functional dimer with HIFβ, leading to activation of the HIF target genes. The central role of HIF-P4Hs in the regulation of the hypoxia response pathway has provided an attractive possibility as a drug candidate for treatment of, e.g., severe anemias and ischemic conditions, and several companies are currently carrying out clinical studies on the use of HIF-P4H inhibitors to treat anemia in patients with a kidney disease. Therefore, it is important to understand the effects of individual HIF-P4H isoenzymes on the hypoxia response and potential other pathways in vivo. The common and specific functions of the HIF-P4H isoenzymes are discussed in this review on the basis of available data from cell biological studies and gene-modified animals.
About the authors
Johanna Myllyharju is Professor of Molecular Biology and the Scientific Director of Biocenter Oulu, University of Oulu. Her research focuses on the key enzymes involved in the regulation of collagen synthesis and hypoxia response. She is a Member of the Academy of Finland Health Sciences Council and a Member of the Management Committee of the EU COST Action TD0901 HypoxiaNet.
Peppi Koivunen is Professor of Medical Biochemistry in the University of Oulu, Finland. Her research focus is 2-oxoglutaratedependent dioxy genases, such as the HIF prolyl 4-hydroxylases, the HIF asparaginyl hydroxylase FIH and a novel transmembrane prolyl 4-hydroxylase, P4H-TM. Koivunen also studies the role of 2-oxoglutarate analogues in cancer, erythropoiesis, ischemia and metabolism.
©2013 by Walter de Gruyter Berlin Boston
Articles in the same Issue
- Masthead
- Masthead
- Guest Editorial
- Highlight: sensing hypoxia in the cell and the organism
- Highlight: Sensing Hypoxia in the Cell and the Organism
- Hypoxia-inducible factor prolyl 4-hydroxylases: common and specific roles
- The regulation, localization, and functions of oxygen-sensing prolyl hydroxylase PHD3
- Deciphering the emerging role of SUMO conjugation in the hypoxia-signaling cascade
- Hypoxia, the HIF pathway and neutrophilic inflammatory responses
- Hydroxylase-dependent regulation of the NF-κB pathway
- Role of hypoxia inducible factor-1α for interferon synthesis in mouse dendritic cells
- Pan-genomic binding of hypoxia-inducible transcription factors
- HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia
- Noninvasive assessment of hypoxia with 3-[18F]-fluoro-1-(2-nitro-1-imidazolyl)-2-propanol ([18F]-FMISO): a PET study in two experimental models of human glioma
- Research Articles/Short Communications
- Protein Structure and Function
- Homo- and heterotypic interactions between Pss proteins involved in the exopolysaccharide transport system in Rhizobium leguminosarum bv. trifolii
- Proteolysis
- Combination of quercetin and tannic acid in inhibiting 26S proteasome affects S5a and 20S expression, and accumulation of ubiquitin resulted in apoptosis in cancer chemoprevention
Articles in the same Issue
- Masthead
- Masthead
- Guest Editorial
- Highlight: sensing hypoxia in the cell and the organism
- Highlight: Sensing Hypoxia in the Cell and the Organism
- Hypoxia-inducible factor prolyl 4-hydroxylases: common and specific roles
- The regulation, localization, and functions of oxygen-sensing prolyl hydroxylase PHD3
- Deciphering the emerging role of SUMO conjugation in the hypoxia-signaling cascade
- Hypoxia, the HIF pathway and neutrophilic inflammatory responses
- Hydroxylase-dependent regulation of the NF-κB pathway
- Role of hypoxia inducible factor-1α for interferon synthesis in mouse dendritic cells
- Pan-genomic binding of hypoxia-inducible transcription factors
- HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia
- Noninvasive assessment of hypoxia with 3-[18F]-fluoro-1-(2-nitro-1-imidazolyl)-2-propanol ([18F]-FMISO): a PET study in two experimental models of human glioma
- Research Articles/Short Communications
- Protein Structure and Function
- Homo- and heterotypic interactions between Pss proteins involved in the exopolysaccharide transport system in Rhizobium leguminosarum bv. trifolii
- Proteolysis
- Combination of quercetin and tannic acid in inhibiting 26S proteasome affects S5a and 20S expression, and accumulation of ubiquitin resulted in apoptosis in cancer chemoprevention
