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

Authors Mennerich D, Dimova EY, Kietzmann T

Received 15 January 2014

Accepted for publication 24 February 2014

Published 30 April 2014 Volume 2014:2 Pages 35—45

DOI https://doi.org/10.2147/HP.S60703

Checked for plagiarism Yes

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Daniela Mennerich,* Elitsa Y Dimova,* Thomas Kietzmann

Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland

*These authors contributed equally to this work

Abstract: 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.

Keywords: HIF-1, phosphorylation, GSK-3β, kinase, hypoxia, ubiquitinylation, tumor suppressor


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