Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1α and mediates its destabilization in a VHL-independent manner

Hypoxia-inducible transcription factor let (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-3 beta 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(x to the proteasome by phosphorylation. Thus, the direct regulation of HIF-1 alpha(x stability by GSK-3 may influence physiological processes or pathophysiological situations such as metabolic diseases or tumors.