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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2014
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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. |
format | Online Article Text |
id | pubmed-5045055 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
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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