Inhibition of GSK3beta by indirubins restores HIF-1alpha accumulation under prolonged periods of hypoxia/anoxia.
Hypoxia inducible factor 1 is regulated by the appearance of the HIF-1alpha subunit. HIF-1alpha is subjected to proteasomal destruction or enhanced protein translation, which requires the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. We investigated how PI3K/Akt and glycogen synthase kinase 3beta (GSK3beta) affect HIF-1alpha in human RKO cells under prolonged periods of severe hypoxia/anoxia. 16- to 32-h lasting incubations attenuated Akt activity and decreased HIF-1alpha protein. This was reproduced by blocking PI3K with LY294002. GSK3beta inhibition by indirubins circumvented the effect of hypoxia/anoxia or LY294002 on HIF-1alpha. Ruling stability regulation of HIF-1alpha protein and/or enhanced transcription of HIF-1alpha mRNA via GSK3beta inhibition out is suggestive for translational modulation of HIF-1alpha under the influence of GSK3beta.
Schnitzer
Steffen E
SE
Department of Cell Biology, Faculty of Biology, University of Kaiserslautern, Erwin Schroedinger Strasse, 67663 Kaiserslautern, Germany.
Schmid
Tobias
T
Zhou
Jie
J
Eisenbrand
Gerhard
G
Brüne
Bernhard
B
D015687:Cell Hypoxia; D002867:Chromones / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D002867:Chromones; D003513:Cycloheximide; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D046988:Proteasome Endopeptidase Complex; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D014157:Transcription Factors; C497442:HIF1A protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C000605506:GSK3B protein, human; C027185:indirubin