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Drug Drug Groups Gene Gene ID Change Interaction Chromosome Clioquinol Approved Vet Approved Withdrawn EPO 2056 upregulated Clioquinol results in increased expression of EPO mRNA 7q22.1 Clioquinol Approved Vet Approved Withdrawn VEGFA 7422 upregulated Clioquinol results in increased expression of VEGFA mRNA 6p21.1