HIF hydroxylation and cellular oxygen sensing
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E. Metzen
Abstract
Hypoxiainducible factor (HIF) is a transcriptional complex that mediates a broad range of cellular and systemic responses to hypoxia. Analysis of HIF-α subunits has demonstrated that its activity is regulated by a series of oxygen-dependent enzymatic hydroxylations at specific prolyl and asparaginyl residues. Combined structural/genetic approaches have identified the relevant enzymes as members of the 2-oxoglutarate-dependent dioxygenase superfamily, possessing a β-barrel 'jelly-roll' conformation that aligns a 2-histidine/1-carboxylate iron coordination motif at the catalytic centre. HIF prolyl hydroxylation is performed by a closely related set of isoenzymes (PHD1-3) that differ in abundance and subcellular localisation. Hydroxylation of either human HIF-1α Pro402 or Pro564 promotes interaction with the von HippelLindau tumour suppressor protein (pVHL). In oxygenated cells this process targets HIFα for rapid proteasomal destruction. HIF asparaginyl hydroxylation is performed by a protein termed factor inhibiting HIF (FIH). In oxygenated cells hydroxylation of human HIF-1α Asn803 prevents interaction with the p300 transcriptional coactivator, providing a second mechanism by which HIFmediated transcription is inactivated. Genetic studies demonstrate a critical function for both types of enzyme in regulating the HIF transcriptional cascade. Limitation of activity in hypoxia supports a central role of these hydroxylases in cellular oxygen sensing. Regulation of the amount of hydroxylase protein, and the supply of other cosubstrates and cofactors, particularly the cellular availability of iron, also contribute to tuning the physiological response to hypoxia.
Copyright © 2004 by Walter de Gruyter GmbH & Co. KG
Articles in the same Issue
- Oxygen and the Cell
- O2 sensing in the human ductus arteriosus: redox-sensitive K+ channels are regulated by mitochondria-derived hydrogen peroxide
- Oxidative stress in the systemic and cellular responses to intermittent hypoxia
- HIF hydroxylation and cellular oxygen sensing
- Visualization of the three-dimensional organization of hypoxia-inducible factor-1α and interacting cofactors in subnuclear structures
- Modulation of glucokinase expression by hypoxia-inducible factor 1 and upstream stimulatory factor 2 in primary rat hepatocytes
- Redox-sensitive regulation of the HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells
- Measurement of exhaled hydrogen peroxide from rabbit lungs
- Effects of reducing agents on glutathione metabolism and the function of carotid body chemoreceptor cells
- Expression of functional purinergic receptors in pulmonary neuroepithelial bodies and their role in hypoxia chemotransmission
- Remodelling of Ca2+ homeostasis in type I cortical astrocytes by hypoxia: evidence for association with Alzheimer's disease
- Simultaneous exposure of rats to dioxin and carbon monoxide reduces the xenobiotic but not the hypoxic response
- Structure and expression of two kininogen genes in mice
- The central domain of the matrix protein of HIV-1: influence on protein structure and virus infectivity
- Skin secretion of the toad Bombina variegata contains multiple insulin-releasing peptides including bombesin and entirely novel insulinotropic structures
- Inhibition of lentil copper/TPQ amine oxidase by the mechanism-based inhibitor derived from tyramine
- Enhanced expression of basolateral multidrug resistance protein isoforms Mrp3 and Mrp5 in rat liver by LPS
- Critical O2 and NO concentrations in NO-induced cell death in a rat liver sinusoidal endothelial cell line
Articles in the same Issue
- Oxygen and the Cell
- O2 sensing in the human ductus arteriosus: redox-sensitive K+ channels are regulated by mitochondria-derived hydrogen peroxide
- Oxidative stress in the systemic and cellular responses to intermittent hypoxia
- HIF hydroxylation and cellular oxygen sensing
- Visualization of the three-dimensional organization of hypoxia-inducible factor-1α and interacting cofactors in subnuclear structures
- Modulation of glucokinase expression by hypoxia-inducible factor 1 and upstream stimulatory factor 2 in primary rat hepatocytes
- Redox-sensitive regulation of the HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells
- Measurement of exhaled hydrogen peroxide from rabbit lungs
- Effects of reducing agents on glutathione metabolism and the function of carotid body chemoreceptor cells
- Expression of functional purinergic receptors in pulmonary neuroepithelial bodies and their role in hypoxia chemotransmission
- Remodelling of Ca2+ homeostasis in type I cortical astrocytes by hypoxia: evidence for association with Alzheimer's disease
- Simultaneous exposure of rats to dioxin and carbon monoxide reduces the xenobiotic but not the hypoxic response
- Structure and expression of two kininogen genes in mice
- The central domain of the matrix protein of HIV-1: influence on protein structure and virus infectivity
- Skin secretion of the toad Bombina variegata contains multiple insulin-releasing peptides including bombesin and entirely novel insulinotropic structures
- Inhibition of lentil copper/TPQ amine oxidase by the mechanism-based inhibitor derived from tyramine
- Enhanced expression of basolateral multidrug resistance protein isoforms Mrp3 and Mrp5 in rat liver by LPS
- Critical O2 and NO concentrations in NO-induced cell death in a rat liver sinusoidal endothelial cell line
