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.
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.
Mesh Terms:
Cell Hypoxia, DNA, Endothelial Growth Factors, Endothelium, Vascular, Enzyme Inhibitors, Gene Expression, HSP90 Heat-Shock Proteins, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Intercellular Signaling Peptides and Proteins, Lactones, Lymphokines, Macrolides, Neovascularization, Pathologic, Oxygen, Receptors, Aryl Hydrocarbon, Transcription Factors, Tumor Cells, Cultured, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors
Cell Hypoxia, DNA, Endothelial Growth Factors, Endothelium, Vascular, Enzyme Inhibitors, Gene Expression, HSP90 Heat-Shock Proteins, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Intercellular Signaling Peptides and Proteins, Lactones, Lymphokines, Macrolides, Neovascularization, Pathologic, Oxygen, Receptors, Aryl Hydrocarbon, Transcription Factors, Tumor Cells, Cultured, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors
Mol. Pharmacol.
Date: Nov. 01, 2002
PubMed ID: 12391259
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