Chun, YS Choi, E Kim, GT Choi, H Kim, CH Lee, MJ Kim, MS Park, JW 2024-01-21T13:44:25Z 2024-01-21T13:44:25Z 2021-09-01 2000-07 0014-2956 https://pubs.kist.re.kr/handle/201004/141276 Cadmium is a substantial industrial and environmental pollutant which seriously impairs erythropoiesis. Cd has been demonstrated to aggravate anemia by suppressing erythropoietin gene expression in anemic patients. As hypoxic induction of erythropoietin mRNA depends on a transcription factor, hypoxia-inducible factor 1 (HIF-1), we hypothesized that Cd suppresses the hypoxic activation of HIF-1. In hypoxic Hep3B cells, all mRNAs of various genes, which are known to be upregulated by HIF-1 activation under hypoxia, were suppressed by Cd in a dose-dependent manner. Cd inhibited the hypoxia-induced activity of luciferase in 293 cells which was transfected with a reporter plasmid carrying a hypoxia response element. By electrophoretic mobility gel shift assay, Cd inhibited the DNA-binding activity of HIF-1 in hypoxic Hep3B cells. Cd reduced the amount of HIF-1 alpha protein in hypoxia, whereas it didn't affect HIF-1 alpha mRNA levels. Moreover, Cd inhibited HIF-1 alpha accumulation induced by cobalt and desferrioxamine. Antioxidants and a proteasome inhibitor prevented the HIF-1 alpha degradation caused by Cd. The possibility that oxidative stress mediates this action of Cd was examined. Cd didn't affect protein oxidation and reduced glutathione levels in hypoxic cells. These results indicate that Cd triggers a redox/proteasome-dependent degradation of HIF-1 alpha protein, reducing HIF-1 activity and in turn suppressing the hypoxic induction of hypoxia-inducible genes. English BLACKWELL SCIENCE LTD FACTOR 1-ALPHA TRANSCRIPTION FACTOR LIPID-PEROXIDATION OXIDATIVE STRESS GENE-EXPRESSION PROTEIN-KINASE FACTOR-I HEME OXYGENASE-1 PATHWAY ACTIVATION Cadmium blocks hypoxia-inducible factor (HIF)-1-mediated response to hypoxia by stimulating the proteasome-dependent degradation of HIF-1 alpha Article 10.1046/j.1432-1327.2000.01453.x 1 EUROPEAN JOURNAL OF BIOCHEMISTRY, v.267, no.13, pp.4198 - 4204 EUROPEAN JOURNAL OF BIOCHEMISTRY 267 13 4198 4204 scie scopus 000087848900034 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article FACTOR 1-ALPHA TRANSCRIPTION FACTOR LIPID-PEROXIDATION OXIDATIVE STRESS GENE-EXPRESSION PROTEIN-KINASE FACTOR-I HEME OXYGENASE-1 PATHWAY ACTIVATION cadmium hypoxia hypoxia-inducible factor 1