Glycogen synthase kinase 3 phosphorylates Hypoxia-Inducible Factor 1 α and mediates its destabilization in a VHL-independent manner

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.