Inhibitory effect of zinc on hypoxic HIF-1 activation in astrocytes.
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.
Kim
Insook
I
BK21 Project for Medical Science, Brain Research Institute, Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
Kim
Chul Hoon
CH
Seo
Gi Ho
GH
Kim
Hyun Soo
HS
Lee
Jinu
J
Kim
Dong Goo
DG
Ahn
Young Soo
YS
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
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