Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1alpha and mediates its destabilization in a VHL-independent manner.
Hypoxia-inducible transcription factor 1alpha (HIF-1alpha) is a key player in the response to hypoxia. Additionally, HIF-1alpha responds to growth factors and hormones which can act via protein kinase B (Akt). However, HIF-1alpha 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-1alpha. We found that the inhibition or depletion of GSK-3 induced HIF-1alpha whereas the overexpression of GSK-3beta reduced HIF-1alpha. These effects were mediated via three amino acid residues in the oxygen-dependent degradation domain of HIF-1alpha. In addition, mutation analyses and experiments with von Hippel-Lindau (VHL)-defective cells indicated that GSK-3 mediates HIF-1alpha 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-1alpha to the proteasome by phosphorylation. Thus, the direct regulation of HIF-1alpha stability by GSK-3 may influence physiological processes or pathophysiological situations such as metabolic diseases or tumors.
Flügel
Daniela
D
Fachbereich Chemie, Abteilung Biochemie, Universität Kaiserslautern, Erwin Schrödinger Str. Geb 54, D-67663 Kaiserslautern, Germany.
Görlach
Agnes
A
Michiels
Carine
C
Kietzmann
Thomas
T
D045744:Cell Line, Tumor; D015536:Down-Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D020218:Response Elements; D015533:Transcriptional Activation / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; D025801:Ubiquitin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D046988:Proteasome Endopeptidase Complex; D018021:Lithium Chloride