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Vol. 62, Issue 5, 975-982, November 2002
/Aryl Hydrocarbon Receptor Nuclear
Translocator DNA Binding by the 90-kDa Heat-Shock Protein Inhibitor
Radicicol
Department of Life Science, University of Seoul, Seoul, Korea
(E.H., S.M.C., S.Y., Y.C., H.P.); Research Center for Proteineous
Materials and School of Dentistry, Chosun University, Gwangju, Korea
(H.-H.K.); Department of Bioscience and Biotechnology, Institute of
Bioscience, Sejong University, Seoul, Korea (J.H.K., H.J.K., M.-O.L.);
and Department of Environmental and Health Chemistry, College of
Pharmacy, Chung-Ang University, Seoul, Korea (D.K.K.)
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 
subunit of hypoxia-inducible factor-1 (HIF-1), which acts as
a heterodimeric trans-activator with the nuclear protein
known as the aryl hydrocarbon receptor nuclear translocator (Arnt). The
resulting heterodimer (HIF-1/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-1 protein and does not inhibit the nuclear localization of
HIF-1. However, this dose of radicicol significantly reduces HRE
binding by the HIF-1/Arnt heterodimer. Our results, the first to
show that radicicol specifically inhibits the interaction between the
HIF-1/Arnt heterodimer and HRE, suggest that Hsp90 modulates the
conformation of the HIF-1/Arnt heterodimer, making it suitable for
interaction with HRE. Furthermore, we demonstrate that radicicol
reduces hypoxia-induced VEGF expression to decrease hypoxia-induced angiogenesis.
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