Abstract
The hypoxia-inducible factor-1α (HIF-1α) subunit is activated in response to lack of oxygen. We found that the Zn-specific chelator, N,N,N′,N′-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) enhances the activity of HIF-1α-proline hydroxylase 2 but the level of HIF-1α protein does not fall because TPEN also inhibits ubiquitination. Since the Zn chelator does not prevent FIH-1 from hydroxylating the asparagine residue of HIF-1α its presence leads to the accumulation of HIF-1α that is both prolyl and asparaginyl hydroxylated and is therefore nonfunctional. In hypoxic cells, TPEN also prevents HIF-1α from interacting with CBP, so reducing expression of HIF-1α target genes. As a result, Zn chelation causes the accumulation of nonfunctional HIF-1α protein in both normoxia and hypoxia. [This study was supported by the Neurobiology Research program grant (2004-01969) from the Ministry of Science and Technology.]
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