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

Eunseon Hur, Hong Hee Kim, Su Mi Choi, Jin Hee Kim, Sujin Yim, Ho Jeong Kwon, Youngyeon Choi, Dae Kyong Kim, Mi Ock Lee, Hyunsung Park

Research output: Contribution to journalArticle

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-1αArnt) 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.

Original languageEnglish (US)
Pages (from-to)975-982
Number of pages8
JournalMolecular Pharmacology
Volume62
Issue number5
DOIs
StatePublished - Nov 1 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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