China
Africa
Explore chapters and articles related to this topic
Vitamin C in Immune Cell Function
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Abel Ang, Margreet C.M. Vissers, Juliet M. Pullar
The hypoxia-induced transcription factors are expressed ubiquitously and are heterodimeric complexes of a constitutively expressed β subunit and a regulatory α subunit (isoforms HIF-1α, HIF-2α, HIF-3α). HIF activation is regulated by posttranslational modification of proline and asparagine residues on the HIF-α proteins [59–61,68]. This reaction is carried out by hydroxylases that are members of the 2-OGDD family [18,68,69]. Proline hydroxylation results in recruitment of von Hippel-Lindau protein and targeting to the proteasome for protein degradation. Asparagine modification prevents the formation of an active transcription complex, and the combined hydroxylation events thereby provide a dual control mechanism to prevent inadvertent activation of HIF-mediated transcription [18,68,69]. Three proline hydroxylases, PHD1-3, and the asparagine hydroxylase known as factor inhibiting HIF (FIH) are grouped together as the HIF hydroxylases and represent a distinct subset of 2-OGGDs with unique oxygen sensing capacity [68,69]. These enzymes have been shown to require ascorbate for optimal activity [70,71]. This dependency has been demonstrated in cell free systems [68,71,72], and other reducing agents such as glutathione are much less effective as recyclers of the hydroxylase active site Fe2+ [71,73–76]. Depleted intracellular ascorbate levels have been shown to contribute to the upregulation of HIF activation, particularly under conditions of mild or moderate hypoxia [70,77].
Overview of Angiogenesis: Molecular and Structural Features
Published in Robert J. Gropler, David K. Glover, Albert J. Sinusas, Heinrich Taegtmeyer, Cardiovascular Molecular Imaging, 2007
Arye Elfenbein, Michael Simons
HIF-1α is degraded under normoxic conditions by a proteosome-dependent pathway, but hypoxia confers stability that enables the protein to accumulate intracellularly. This occurs because the baseline degradation of HIF-1α depends on its post-translational modification, a process that requires oxygen as a cofactor. The Von Hippel-Lindau protein (a member of the ubiquitin ligase family) marks HIF-1α for subsequent degradation only if HIF-1α is post-translationally modified by prolyl hydroxylase-containing enzymes (4). By requiring oxygen (as well as ascorbic acid and iron), prolyl hydroxylase function ultimately results in the modulation of intracellular HIF-1α concentration. Under hypoxic conditions, hydroxylation of HIF-1α is therefore ineffective, the protein becomes less readily degraded, and it subsequently accumulates in the cell.
Altitude, temperature, circadian rhythms and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Henning Wackerhage, Kenneth A. Dyar, Martin Schönfelder
Oxygen is not only sensed by the carotid body but also by many cells in the human body through the activation of transcription factors called hypoxia-inducible factors (HIFs), discovered by Nobel Prize winner Greg Semenza (Box 11.1). HIF-1 is a transcriptional complex formed from heterodimers of oxygen-sensitive alpha (HIF-1α, HIF-2α) and beta (HIF-1β) subunits. When the oxygen tension drops inside the cell, cytosolic HIF-1α or HIF-2α proteins are stabilised and can translocate into the nucleus to form heterodimers with nuclear HIF-1β proteins. Accumulating HIF heterodimers then drive expression of genes such as red blood cell development-promoting erythropoietin (EPO) or genes that promote angiogenesis, such as vascular endothelial growth factor (VEGF). Hypoxia induces gene expression through HIFs by three steps (6, 9, 10): Hypoxia inactivates the prolyl hydroxylases PHD1–3: PHD1–3 are oxygen-activated enzymes that add an OH-group (hydroxylation) to proline amino acids on other proteins. Thus, under hypoxia, PHD1–3 hydroxylate their targets less.Hypoxia reduces HIF-1 α hydroxylation: When the oxygen tension drops, PHD1–3 hydroxylate HIF-1α less frequently at Pro402 or Pro564, whereas HIF-2α hydroxylation is reduced on Pro405 and Pro531. Additionally, during hypoxia the asparaginyl hydroxylase FIH-1 reduces the hydroxylation of HIF-1α at Asn803 and HIF-2α at Asn847, which increases the activity of HIF-1. Furthermore, all this is stimulated by iron (Fe2+).Hypoxia reduces HIF-1α degradation, resulting in a rise of HIF-1 α: Under normoxia, hydroxylated HIF-1α or HIF-2α bind to the von Hippel-Lindau protein (pVHL) E3 ubiquitin ligase complex. This complex adds ubiquitin groups to HIF-1α and HIF-2α, targeting them for degradation by the protein-digesting proteasome. Therefore, HIF-1α levels remain low when there is enough oxygen. In contrast, hypoxia reduces HIF-1α hydroxylation and degradation, resulting in an increase of HIF-1α.The transcription factor HIF-1 regulates the adaptation to hypoxia: Under hypoxia, the HIF-1α concentration is relatively high. HIF-1α and HIF-1β then heterodimerise to form the active transcription factor HIF-1. HIF-1 then binds to G/ACGTG DNA motifs known as the hypoxia-response element (HRE) and activates transcription of hypoxia-induced genes such as erythropoietin (EPO). See Figure 11.2 for an overview of HIF-1’s regulation of gene expression.
Investigational hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) for the treatment of anemia associated with chronic kidney disease
Published in Expert Opinion on Investigational Drugs, 2018
Lucia Del Vecchio, Francesco Locatelli
The HIF system is tightly regulated by a class of O2-sensitive enzymes, the prolyl-hydroxyl domain (PHD). They belong to a family of dioxygenase enzymes that require oxygen, iron, and 2-oxyglutarate (2-OG) for their catalytic activity. In normal O2 conditions, the PHD hydroxylates the HIFα subunit, which in turn binds to the von Hippel-Lindau protein–elongin B/C complex and is then fast degraded by proteasomes [23]. PHD degradation is very effective: in normal oxygen conditions, HIFα half-life is of only 5 min. Conversely, under hypoxic conditions, PHD activity decreases due to the lack of one of its main co-substrate; HIFα can then bind to the HIFβ subunit, translocate into the nucleus, and master the physiological response of the body to hypoxia.
Roxadustat in the treatment of anaemia in chronic kidney disease
Published in Expert Opinion on Investigational Drugs, 2018
Lucia Del Vecchio, Francesco Locatelli
PHDs belong to a family of dioxygenase enzymes that require oxygen, iron, and 2-oxyglutarate (2-OG) for their catalytic activity. They split O2 and couple oxidation (hydroxylation) of HIF-α to oxidative decarboxylation of 2-OG to succinate and CO2. Both iron and oxygen promote the binding of HIFα to the von Hippel–Lindau protein–elongin B/C complex and then signaling for proteosomal degradation of HIFα [18]. Under normal oxygen conditions, HIF-α half-life is of approximately 5 min as a consequence of PHD degradation. By contrast, under hypoxia, PHD activity decreases and HIF-α accumulates. HIF-α can then bind to the HIF-β subunit (also known as ARNT, resulting in the activation of a large array of target hypoxia-responsive genes [19].
Fumarate hydratase as a therapeutic target in renal cancer
Published in Expert Opinion on Therapeutic Targets, 2020
Priyanka Kancherla, Michael Daneshvar, Rebecca A. Sager, Mehdi Mollapour, Gennady Bratslavsky
The Warburg effect in HLRCC is accompanied by the activation of hypoxic pathways under normoxic conditions. This pseudohypoxic drive is central to tumorigenesis in HLRCC as well as other renal cell carcinomas and is similar to the one clearly demonstrated in clear cell renal cell carcinoma (ccRCC) [37]. Mutated in a high percentage of both sporadic and inherited ccRCC cases, the von Hippel–Lindau protein (VHL) has a key role in regulating hypoxic pathways. VHL is the recognition subunit of an E3 ubiquitin ligase protein complex that targets intracellular proteins for proteasomal degradation.