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Molecular and Cellular Biology, May 2007, p. 3253-3265, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.00015-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Glycogen Synthase Kinase 3 Phosphorylates Hypoxia-Inducible Factor 1{alpha} and Mediates Its Destabilization in a VHL-Independent Manner{triangledown}

Daniela Flügel,1 Agnes Görlach,2 Carine Michiels,3 and Thomas Kietzmann1*

Fachbereich Chemie, Abteilung Biochemie, Universität Kaiserslautern, D-67663 Kaiserslautern, Germany,1 Experimental Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich at the Technical University Munich, Lazarettstrasse 36, 80636 Munich, Germany,2 Laboratory of Biochemistry and Cellular Biology, University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium3

Received 3 January 2007/ Returned for modification 12 February 2007/ Accepted 13 February 2007

Hypoxia-inducible transcription factor 1{alpha} (HIF-1{alpha}) is a key player in the response to hypoxia. Additionally, HIF-1{alpha} responds to growth factors and hormones which can act via protein kinase B (Akt). However, HIF-1{alpha} is not a direct substrate for this kinase. Therefore, we investigated whether the protein kinase B target glycogen synthase kinase 3 (GSK-3) may have an impact on HIF-1{alpha}. We found that the inhibition or depletion of GSK-3 induced HIF-1{alpha} whereas the overexpression of GSK-3ß reduced HIF-1{alpha}. These effects were mediated via three amino acid residues in the oxygen-dependent degradation domain of HIF-1{alpha}. In addition, mutation analyses and experiments with von Hippel-Lindau (VHL)-defective cells indicated that GSK-3 mediates HIF-1{alpha} degradation in a VHL-independent manner. In line with these observations, the inhibition of the proteasome reversed the GSK-3 effects, indicating that GSK-3 may target HIF-1{alpha} to the proteasome by phosphorylation. Thus, the direct regulation of HIF-1{alpha} stability by GSK-3 may influence physiological processes or pathophysiological situations such as metabolic diseases or tumors.

* Corresponding author. Mailing address: Fachbereich Chemie, Abteilung Biochemie, Universität Kaiserslautern, Erwin Schrödinger Str. Geb 54, D-67663 Kaiserslautern, Germany. Phone: 49-631-2054953. Fax: 49-631-2053419. E-mail: tkietzm{at}gwdg.de

{triangledown} Published ahead of print on 26 February 2007.

Molecular and Cellular Biology, May 2007, p. 3253-3265, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.00015-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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