@article {Hur975, author = {Eunseon Hur and Hong-Hee Kim and Su Mi Choi and Jin Hee Kim and Sujin Yim and Ho Jeong Kwon and Youngyeon Choi and Dae Kyong Kim and Mi-Ock Lee and Hyunsung Park}, title = {Reduction of Hypoxia-Induced Transcription through the Repression of Hypoxia-Inducible Factor-1α/Aryl Hydrocarbon Receptor Nuclear Translocator DNA Binding by the 90-kDa Heat-Shock Protein Inhibitor Radicicol}, volume = {62}, number = {5}, pages = {975--982}, year = {2002}, doi = {10.1124/mol.62.5.975}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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 α subunit of hypoxia-inducible factor-1 (HIF-1α), which acts as a heterodimeric trans-activator with the nuclear protein known as the aryl hydrocarbon receptor nuclear translocator (Arnt). The resulting heterodimer (HIF-1α/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 μg/ml) does not significantly change the stability of the HIF-1α protein and does not inhibit the nuclear localization of HIF-1α. However, this dose of radicicol significantly reduces HRE binding by the HIF-1α/Arnt heterodimer. Our results, the first to show that radicicol specifically inhibits the interaction between the HIF-1α/Arnt heterodimer and HRE, suggest that Hsp90 modulates the conformation of the HIF-1α/Arnt heterodimer, making it suitable for interaction with HRE. Furthermore, we demonstrate that radicicol reduces hypoxia-induced VEGF expression to decrease hypoxia-induced angiogenesis.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/62/5/975}, eprint = {https://molpharm.aspetjournals.org/content/62/5/975.full.pdf}, journal = {Molecular Pharmacology} }