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• W2080775051 endingPage "13513" @default.
• W2080775051 startingPage "13506" @default.
• W2080775051 abstract "Hypoxia inducible factor 1 (HIF-1), a heterodimeric transcription factor composed of HIF-1α and HIF-1β subunits, serves as a key regulator of metabolic adaptation to hypoxia. The amount of HIF-1α protein is regulated either by attenuating von Hippel-Lindau protein (pVHL)-dependent ubiquitination and subsequent 26 S proteasomal degradation or by enhancing cap-dependent mRNA translation, presumably involving a phosphatidyinositol 3-kinase (PI3K)/Akt-regulated pathway. In addition, it became apparent that Hsp90 protects HIF-1α from oxygen-independent degradation. Here we present evidence that PI3K/Akt is required for heat shock proteins to stabilize HIF-1α. In pVHL-deficient renal cell carcinoma cells, PI3K inhibition by LY294002 and wortmannin or transfection of either a dominant negative PI3K or a kinase-dead Akt mutant substantially lowered constitutively expressed HIF-1α without altering HIF-1α mRNA. Inhibitors of mitogen-activated protein kinase kinase (MAPKK) such as PD98059 or the p38 MAPK inhibitor SB203580 showed no interference. Considering that PI3K inhibitors down-regulated heat shock protein 90 (Hsp90) as well as Hsp70 expression and moreover attenuated heat- or hypoxia-induced Hsp70 as well as hypoxia-induced Hsp90 up-regulation we conclude that PI3K inhibition promoted degradation of HIF-1α indirectly by reducing steady state concentrations of Hsp90 and/or Hsp70. HIF-1α co-immunoprecipitated with Hsp90/Hsp70 and direct binding of Hsp70 to the oxygen-dependent degradation domain (ODD) of HIF-1α was proven by a pull-down assay and a peptide array. PI3K-mediated degradation of HIF-1α was confirmed in HEK 293 cells under hypoxia, suggesting that heat shock proteins constitute an integral component for HIF-1α accumulation. We conclude that PI3K/Akt contributes to HIF-1α stabilization by provoking expression of heat shock proteins." @default.
• W2080775051 created "2016-06-24" @default.
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• W2080775051 date "2004-04-01" @default.
• W2080775051 modified "2023-10-16" @default.
• W2080775051 title "PI3K/Akt Is Required for Heat Shock Proteins to Protect Hypoxia-inducible Factor 1α from pVHL-independent Degradation" @default.
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• W2080775051 doi "https://doi.org/10.1074/jbc.m310164200" @default.
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• W2080775051 hasPublicationYear "2004" @default.
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