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Title:
PHD1-3 oxygen sensors in vivo—lessons learned from gene deletions | Pflügers Archiv - European Journal of Physiology
Description:
Oxygen sensors enable cells to adapt to limited oxygen availability (hypoxia), affecting various cellular and tissue responses. Prolyl-4-hydroxylase domain 1–3 (PHD1-3; also called Egln1-3, HIF-P4H 1–3, HIF-PH 1–3) proteins belong to the Fe2+- and 2-oxoglutarate-dependent dioxygenase superfamily and utilise molecular oxygen (O2) alongside 2-oxoglutarate as co-substrate to hydroxylate two proline residues of α subunits of the dimeric hypoxia inducible factor (HIF) transcription factor. PHD1-3-mediated hydroxylation of HIF-α leads to its degradation and inactivation. Recently, various PHD inhibitors (PHI) have entered the clinics for treatment of renal anaemia. Pre-clinical analyses indicate that PHI treatment may also be beneficial in numerous other hypoxia-associated diseases. Nonetheless, the underlying molecular mechanisms of the observed protective effects of PHIs are only partly understood, currently hindering their translation into the clinics. Moreover, the PHI-mediated increase of Epo levels is not beneficial in all hypoxia-associated diseases and PHD-selective inhibition may be advantageous. Here, we summarise the current knowledge about the relevance and function of each of the three PHD isoforms in vivo, based on the deletion or RNA interference-mediated knockdown of each single corresponding gene in rodents. This information is crucial for our understanding of the physiological relevance and function of the PHDs as well as for elucidating their individual impact on hypoxia-associated diseases. Furthermore, this knowledge highlights which diseases may best be targeted by PHD isoform-selective inhibitors in case such pharmacologic substances become available.
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Keywords {🔍}

phd, pubmed, mice, article, google, scholar, cas, deletion, increased, central, cells, hydroxylase, hifα, prolyl, cell, reduced, injury, hif, expression, protective, effect, enhanced, decreased, model, inactivation, function, hypoxia, activity, factor, development, muscle, inhibition, levels, oxygen, cardiac, regulation, protein, gene, liver, bone, domain, response, endothelial, hypoxiainducible, fibrosis, treatment, conditional, induced, size, cancer,

Topics {✒️}

hypoxia-inducible factor prolyl-4-hydroxylase-1 hypoxia-inducible factor prolyl-4-hydroxylation pflügers archiv—european journal hepatic phd2/hif-1alpha axis article download pdf high-sucrose diet-induced gluconeogenesis muscle-derived stem/progenitor cells creb-regulated transcriptional coactivator hypoxia-inducible factor 1-alpha hypoxia-inducible factor-2alpha hypoxia-inducible factor 1alpha β-cell-specific phd1 deletion superior cervical ganglion hif-alpha-prolyl-4-hydroxylases prolyl-4-hydroxylase domain 1–3 prolyl-4-hydroxylase domain prolyl hydroxylase domain prolyl-4-hydroxylase domain 3 pancreatic beta-cell function von hippel-lindau protein hypertension-induced cardiovascular remodelling mediates oxygen-induced retinopathy individual prolyl-4-hydroxylase isoforms low-density lipoprotein receptor reduced intra-plague haemorrhage neuron-specific phd2 inactivation obstructive sleep apnoea reduced hypoxia-mediated stimulation chicken-β-actin-creer chicken β-actin-creer astrocytic oxygen-sensing mechanism cardiomyocyte-specific transgenic expression bile duct injury-mediated radiation-induced gastrointestinal toxicity prolyl hydroxylated hif-1α angii-mediated renal fibrosis constitutive cardiac-specific deletion targeting hypoxia-inducible factors type 2 collagen-α1-cre alcohol-induced liver damage foxd1-lineage mesodermal cells cd68-cre-mediated phd2 deletion friedrich-ludwig-jahn-str venous thrombus neovascularisation autoregulatory oxygen-sensing system /r-mediated renal injury hif-2alpha/notch3 pathways endothelial-specific phd2 ko elevated β-cell apoptosis endothelial hif-2alpha contributes

Questions {❓}

Bersten DC, Peet DJ (2019) When is a target not a target?
Faivre A, Scholz CC, de Seigneux S (2021) Hypoxia in chronic kidney disease: towards a paradigm shift?
Gaete D, Rodriguez D, Watts D, Sormendi S, Chavakis T, Wielockx B (2021) HIF-prolyl hydroxylase domain proteins (PHDs) in cancer-potential targets for anti-tumor therapy?
Strowitzki MJ, Cummins EP, Taylor CT (2019) Protein hydroxylation by hypoxia-inducible factor (HIF) hydroxylases: unique or ubiquitous?

Schema {🗺️}

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         headline:PHD1-3 oxygen sensors in vivo—lessons learned from gene deletions
         description:Oxygen sensors enable cells to adapt to limited oxygen availability (hypoxia), affecting various cellular and tissue responses. Prolyl-4-hydroxylase domain 1–3 (PHD1-3; also called Egln1-3, HIF-P4H 1–3, HIF-PH 1–3) proteins belong to the Fe2+- and 2-oxoglutarate-dependent dioxygenase superfamily and utilise molecular oxygen (O2) alongside 2-oxoglutarate as co-substrate to hydroxylate two proline residues of α subunits of the dimeric hypoxia inducible factor (HIF) transcription factor. PHD1-3-mediated hydroxylation of HIF-α leads to its degradation and inactivation. Recently, various PHD inhibitors (PHI) have entered the clinics for treatment of renal anaemia. Pre-clinical analyses indicate that PHI treatment may also be beneficial in numerous other hypoxia-associated diseases. Nonetheless, the underlying molecular mechanisms of the observed protective effects of PHIs are only partly understood, currently hindering their translation into the clinics. Moreover, the PHI-mediated increase of Epo levels is not beneficial in all hypoxia-associated diseases and PHD-selective inhibition may be advantageous. Here, we summarise the current knowledge about the relevance and function of each of the three PHD isoforms in vivo, based on the deletion or RNA interference-mediated knockdown of each single corresponding gene in rodents. This information is crucial for our understanding of the physiological relevance and function of the PHDs as well as for elucidating their individual impact on hypoxia-associated diseases. Furthermore, this knowledge highlights which diseases may best be targeted by PHD isoform-selective inhibitors in case such pharmacologic substances become available.
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            Human Physiology
            Molecular Medicine
            Neurosciences
            Cell Biology
            Receptors
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      headline:PHD1-3 oxygen sensors in vivo—lessons learned from gene deletions
      description:Oxygen sensors enable cells to adapt to limited oxygen availability (hypoxia), affecting various cellular and tissue responses. Prolyl-4-hydroxylase domain 1–3 (PHD1-3; also called Egln1-3, HIF-P4H 1–3, HIF-PH 1–3) proteins belong to the Fe2+- and 2-oxoglutarate-dependent dioxygenase superfamily and utilise molecular oxygen (O2) alongside 2-oxoglutarate as co-substrate to hydroxylate two proline residues of α subunits of the dimeric hypoxia inducible factor (HIF) transcription factor. PHD1-3-mediated hydroxylation of HIF-α leads to its degradation and inactivation. Recently, various PHD inhibitors (PHI) have entered the clinics for treatment of renal anaemia. Pre-clinical analyses indicate that PHI treatment may also be beneficial in numerous other hypoxia-associated diseases. Nonetheless, the underlying molecular mechanisms of the observed protective effects of PHIs are only partly understood, currently hindering their translation into the clinics. Moreover, the PHI-mediated increase of Epo levels is not beneficial in all hypoxia-associated diseases and PHD-selective inhibition may be advantageous. Here, we summarise the current knowledge about the relevance and function of each of the three PHD isoforms in vivo, based on the deletion or RNA interference-mediated knockdown of each single corresponding gene in rodents. This information is crucial for our understanding of the physiological relevance and function of the PHDs as well as for elucidating their individual impact on hypoxia-associated diseases. Furthermore, this knowledge highlights which diseases may best be targeted by PHD isoform-selective inhibitors in case such pharmacologic substances become available.
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      dateModified:2024-03-21T00:00:00Z
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      keywords:
         Hypoxia
         Egln
         HIF
         Hydroxylase inhibitor
         Mouse
         Knockout
         Human Physiology
         Molecular Medicine
         Neurosciences
         Cell Biology
         Receptors
      image:
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