Clioquinol, a Cu(II)/Zn(II) chelator, inhibits both ubiquitination and asparagine hydroxylation of hypoxia-inducible factor-1alpha, leading to expression of vascular endothelial growth factor and erythropoietin in normoxic cells.

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Choi SM, Choi KO, Park YK, Cho H, Yang EG, Park H

J Biol Chem. 2006 Nov 10;281(45):34056-63. Epub 2006 Sep 13.

PubMed ID

16973622 [ View in PubMed

]

Abstract

We found that the Cu(II) and Zn(II)-specific chelator Clioquinol (10-50 microM) increased functional hypoxia-inducible factor 1alpha (HIF-1alpha) protein, leading to increased expression of its target genes, vascular endothelial growth factors and erythropoietin, in SH-SY5Y cells and HepG2 cells. Clioquinol inhibited ubiquitination of HIF-1alpha in a Cu(II)- and Zn(II)-dependent manner. It prevents FIH-1 from hydroxylating the asparagine residue (803) of HIF-1alpha in a Cu(II)- and Zn(II)-independent fashion. Therefore, it leads to the accumulation of HIF-1alpha that is prolyl but not asparaginyl hydroxylated. Consistent with this, co-immunoprecipitation assays showed that Clioquinol-induced HIF-1alpha interacted with cAMP-responsive element-binding protein in normoxic cells, implying that Clioquinol stabilizes the trans-active form of HIF-1alpha. Our results indicate that Clioquinol could be useful as an inducer of HIF-1alpha and its target genes in ischemic diseases.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Hypoxia-inducible factor 1-alpha	Q16665	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Clioquinol	Approved Vet Approved Withdrawn	EPO	2056	upregulated	Clioquinol results in increased expression of EPO mRNA	7q22.1
Clioquinol	Approved Vet Approved Withdrawn	VEGFA	7422	upregulated	Clioquinol results in increased expression of VEGFA mRNA	6p21.1