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Direct phosphorylation events involved in HIF-α regulation: the role of GSK-3β

Hypoxia-inducible factors (HIFs), consisting of α- and β-subunits, are critical regulators of the transcriptional response to hypoxia under both physiological and pathological conditions. To a large extent, the protein stability and the recruitment of coactivators to the C-terminal transactivation d...

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Detalles Bibliográficos
Autores principales: Mennerich, Daniela, Dimova, Elitsa Y, Kietzmann, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045055/
https://www.ncbi.nlm.nih.gov/pubmed/27774465
http://dx.doi.org/10.2147/HP.S60703
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author Mennerich, Daniela
Dimova, Elitsa Y
Kietzmann, Thomas
author_facet Mennerich, Daniela
Dimova, Elitsa Y
Kietzmann, Thomas
author_sort Mennerich, Daniela
collection PubMed
description Hypoxia-inducible factors (HIFs), consisting of α- and β-subunits, are critical regulators of the transcriptional response to hypoxia under both physiological and pathological conditions. To a large extent, the protein stability and the recruitment of coactivators to the C-terminal transactivation domain of the HIF α-subunits determine overall HIF activity. The regulation of HIF α-subunit protein stability and coactivator recruitment is mainly achieved by oxygen-dependent posttranslational hydroxylation of conserved proline and asparagine residues, respectively. Under hypoxia, the hydroxylation events are inhibited and HIF α-subunits stabilize, translocate to the nucleus, dimerize with the β-subunits, and trigger a transcriptional response. However, under normal oxygen conditions, HIF α-subunits can be activated by various growth and coagulation factors, hormones, cytokines, or stress factors implicating the involvement of different kinase pathways in their regulation, thereby making HIF-α-regulating kinases attractive therapeutic targets. From the kinases known to regulate HIF α-subunits, only a few phosphorylate HIF-α directly. Here, we review the direct phosphorylation of HIF-α with an emphasis on the role of glycogen synthase kinase-3β and the consequences for HIF-1α function.
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spelling pubmed-50450552016-10-21 Direct phosphorylation events involved in HIF-α regulation: the role of GSK-3β Mennerich, Daniela Dimova, Elitsa Y Kietzmann, Thomas Hypoxia (Auckl) Review Hypoxia-inducible factors (HIFs), consisting of α- and β-subunits, are critical regulators of the transcriptional response to hypoxia under both physiological and pathological conditions. To a large extent, the protein stability and the recruitment of coactivators to the C-terminal transactivation domain of the HIF α-subunits determine overall HIF activity. The regulation of HIF α-subunit protein stability and coactivator recruitment is mainly achieved by oxygen-dependent posttranslational hydroxylation of conserved proline and asparagine residues, respectively. Under hypoxia, the hydroxylation events are inhibited and HIF α-subunits stabilize, translocate to the nucleus, dimerize with the β-subunits, and trigger a transcriptional response. However, under normal oxygen conditions, HIF α-subunits can be activated by various growth and coagulation factors, hormones, cytokines, or stress factors implicating the involvement of different kinase pathways in their regulation, thereby making HIF-α-regulating kinases attractive therapeutic targets. From the kinases known to regulate HIF α-subunits, only a few phosphorylate HIF-α directly. Here, we review the direct phosphorylation of HIF-α with an emphasis on the role of glycogen synthase kinase-3β and the consequences for HIF-1α function. Dove Medical Press 2014-04-30 /pmc/articles/PMC5045055/ /pubmed/27774465 http://dx.doi.org/10.2147/HP.S60703 Text en © 2014 Mennerich et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Review
Mennerich, Daniela
Dimova, Elitsa Y
Kietzmann, Thomas
Direct phosphorylation events involved in HIF-α regulation: the role of GSK-3β
title Direct phosphorylation events involved in HIF-α regulation: the role of GSK-3β
title_full Direct phosphorylation events involved in HIF-α regulation: the role of GSK-3β
title_fullStr Direct phosphorylation events involved in HIF-α regulation: the role of GSK-3β
title_full_unstemmed Direct phosphorylation events involved in HIF-α regulation: the role of GSK-3β
title_short Direct phosphorylation events involved in HIF-α regulation: the role of GSK-3β
title_sort direct phosphorylation events involved in hif-α regulation: the role of gsk-3β
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045055/
https://www.ncbi.nlm.nih.gov/pubmed/27774465
http://dx.doi.org/10.2147/HP.S60703
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