title: Inhibitory effect of zinc on hypoxic HIF-1 activation in astrocytes.
abstract: Hypoxia-inducible factor-1 (HIF-1) regulates the expression of neuroprotective genes such as erythropoietin (EPO). We investigated the mechanism by which zinc, an excitotoxin-like metal, regulates HIF-1 under hypoxic conditions in astrocytes. In hypoxic LN215 cells, HIF-1alpha stabilized and accumulated in the nucleus, resulting in an increase in its DNA-binding activity to the EPO enhancer. Zinc inhibited hypoxia-induced increases in HIF-1 DNA-binding activity and the HIF-1-dependent mRNA expression of EPO. Zinc did not affect hypoxic stabilization of HIF-1alpha. Nuclear migration of HIF-1alpha upon hypoxia was reduced by zinc. Complete blockade of hypoxia-induced assembly of HIF-1alpha-HIF-1beta complex was observed after treatment of zinc. These findings suggest that zinc hampers hypoxia-stimulated HIF-1 activation in astrocytes by inhibiting nuclear HIF-1alpha translocation and subsequently disrupting HIF-1 heterodimerization.
authors.affiliation: BK21 Project for Medical Science, Brain Research Institute, Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Insook
authors.initials: I
authors.lastname: Kim
authors.forename: Chul Hoon
authors.initials: CH
authors.lastname: Kim
authors.forename: Gi Ho
authors.initials: GH
authors.lastname: Seo
authors.forename: Hyun Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: Jinu
authors.initials: J
authors.lastname: Lee
authors.forename: Dong Goo
authors.initials: DG
authors.lastname: Kim
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Ahn
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001254:Astrocytoma / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors; D019287:Zinc Sulfate / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013859:Thiocarbamates; D004921:Erythropoietin; C066229:prolinedithiocarbamate; D019287:Zinc Sulfate; D011392:Proline