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Inhibition of GSK3β by indirubins restores HIF‐1α accumulation under prolonged periods of hypoxia/anoxia
Author(s) -
Schnitzer Steffen E.,
Schmid Tobias,
Zhou Jie,
Eisenbrand Gerhard,
Brüne Bernhard
Publication year - 2005
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2004.12.023
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , gsk 3 , hypoxia (environmental) , ly294002 , gsk3b , glycogen synthase , phosphatidylinositol , chemistry , kinase , g alpha subunit , messenger rna , microbiology and biotechnology , protein subunit , phosphorylation , signal transduction , biology , biochemistry , gene , oxygen , organic chemistry
Hypoxia inducible factor 1 is regulated by the appearance of the HIF‐1α subunit. HIF‐1α 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 3β (GSK3β) affect HIF‐1α in human RKO cells under prolonged periods of severe hypoxia/anoxia. 16‐ to 32‐h lasting incubations attenuated Akt activity and decreased HIF‐1α protein. This was reproduced by blocking PI3K with LY294002. GSK3β inhibition by indirubins circumvented the effect of hypoxia/anoxia or LY294002 on HIF‐1α. Ruling stability regulation of HIF‐1α protein and/or enhanced transcription of HIF‐1α mRNA via GSK3β inhibition out is suggestive for translational modulation of HIF‐1α under the influence of GSK3β.