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

Daniela Flügel, Agnes Görlach, Carine Michiels, Thomas Kietzmann

Research output: Contribution to journalArticlepeer-review

216 Scopus citations

Abstract

Hypoxia-inducible transcription factor 1α (HIF-1α) is a key player in the response to hypoxia. Additionally, HIF-1α responds to growth factors and hormones which can act via protein kinase B (AM). However, HIF-1α 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-1α. We found that the inhibition or depletion of GSK-3 induced HIF-1α whereas the overexpression of GSK-3β reduced HIF-1α. These effects were mediated via three amino acid residues in the oxygen-dependent degradation domain of HIF-1α. In addition, mutation analyses and experiments with von Hippel-Lindau (VHL)-defective cells indicated that GSK-3 mediates HIF-1α 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-1α to the proteasome by phosphorylation. Thus, the direct regulation of HIF-1α stability by GSK-3 may influence physiological processes or pathophysiological situations such as metabolic diseases or tumors.

Original languageEnglish
Pages (from-to)3253-3265
Number of pages13
JournalMolecular and Cellular Biology
Volume27
Issue number9
DOIs
StatePublished - May 2007

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