title: Reduction of hypoxia-induced transcription through the repression of hypoxia-inducible factor-1alpha/aryl hydrocarbon receptor nuclear translocator DNA binding by the 90-kDa heat-shock protein inhibitor radicicol.
abstract: Under low oxygen tension, cells increase the transcription of specific genes involved in angiogenesis, erythropoiesis, and glycolysis. Hypoxia-induced gene expression depends primarily on stabilization of the alpha subunit of hypoxia-inducible factor-1 (HIF-1alpha), which acts as a heterodimeric trans-activator with the nuclear protein known as the aryl hydrocarbon receptor nuclear translocator (Arnt). The resulting heterodimer (HIF-1alpha/Arnt) interacts specifically with the hypoxia-responsive element (HRE), thereby increasing transcription of the genes under HRE control. Our results indicate that the 90-kDa heat-shock protein (Hsp90) inhibitor radicicol reduces the hypoxia-induced expression of both endogenous vascular endothelial growth factor (VEGF) and HRE-driven reporter plasmids. Radicicol treatment (0.5 microg/ml) does not significantly change the stability of the HIF-1alpha protein and does not inhibit the nuclear localization of HIF-1alpha. However, this dose of radicicol significantly reduces HRE binding by the HIF-1alpha/Arnt heterodimer. Our results, the first to show that radicicol specifically inhibits the interaction between the HIF-1alpha/Arnt heterodimer and HRE, suggest that Hsp90 modulates the conformation of the HIF-1alpha/Arnt heterodimer, making it suitable for interaction with HRE. Furthermore, we demonstrate that radicicol reduces hypoxia-induced VEGF expression to decrease hypoxia-induced angiogenesis.
authors.affiliation: Department of Life Science, University of Seoul, Tongdaemun-gu, Seoul, Korea.
authors.forename: Eunseon
authors.initials: E
authors.lastname: Hur
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
authors.forename: Su Mi
authors.initials: SM
authors.lastname: Choi
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: Sujin
authors.initials: S
authors.lastname: Yim
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Youngyeon
authors.initials: Y
authors.lastname: Choi
authors.forename: Dae Kyong
authors.initials: DK
authors.lastname: Kim
authors.forename: Mi-Ock
authors.initials: MO
authors.lastname: Lee
authors.forename: Hyunsung
authors.initials: H
authors.lastname: Park
mesh_terms: D015687:Cell Hypoxia; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology*; D008222:Lymphokines / Q000378:metabolism; D018942:Macrolides; D009389:Neovascularization, Pathologic; D010100:Oxygen / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D007783:Lactones; D008222:Lymphokines; D018942:Macrolides; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004247:DNA; C035359:monorden; D010100:Oxygen