Abstract
In the course of our screening, we discovered a novel compound, A-503451A, as a potent hypoxia-inducible factor (HIF) activator. In human hepatocarcinoma HepG2 cells, A-503451A induced HIF-mediated luciferase reporter gene expression and stabilized HIF-1α protein. A-503451A increased the mRNA expression levels and the protein secretion of HIF-dependent genes, vascular endothelial growth factor and erythropoietin. Addition of excess ferric chloride to the culture medium suppressed the HIF-induction activity of A-503451A. A-503451A did not have iron-chelating activity in vitro, but decreased the intracellular labile iron pool concentration. These data indicate that A-503451A is a unique HIF activator.
MeSH terms
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Culture Media / chemistry
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Erythropoietin / genetics
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Erythropoietin / metabolism
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Fermentation
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Gene Expression Regulation
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Genes, Reporter
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Hep G2 Cells
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / agonists*
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Indoles / chemistry
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Indoles / pharmacology*
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Iron Chelating Agents / chemistry
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Iron Chelating Agents / pharmacology*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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A-503451A
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Culture Media
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EPO protein, human
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Indoles
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Iron Chelating Agents
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RNA, Messenger
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Erythropoietin