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

Mi Choi Su, Kyung Ok Choi, Young Kwon Park, Hyunju Cho, Gyeong Yang Eun, Hyunsung Park

Research output: Contribution to journalArticlepeer-review

Abstract

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

Original languageEnglish (US)
Pages (from-to)34056-34063
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number45
DOIs
StatePublished - Nov 10 2006
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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