Suppression of erythropoietin gene expression by cadmium depends on inhibition of HIF-1, not stimulation of GATA-2

Naoshi Obara, Shigehiko Imagawa, Yoko Nakano, Norio Suzuki, Masayuki Yamamoto, Toshiro Nagasawa

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)


Long-term exposure of rats to cadmium (Cd) resulted in a marked suppression of erythropoietin (Epo) mRNA expression in the kidneys and the development of severe anemia. A recent report revealed that Cd inhibited hypoxia-inducible factor 1 (HIF-1) binding activity and Epo mRNA expression and protein production. However, Epo gene expression is also regulated by transcription factor GATA-2, which binds to the GATA binding site of the Epo promoter. To elucidate the mechanism of suppression of Epo by Cd, the effect of Cd on GATA-2 function was studied. Epo promoter/enhancer luciferase constructs, one with the wild-type promoter and another with a promoter with a mutant GATA site, were transfected into Hep3B zcells. No significant difference in Epo promoter activity in these two types of cells was observed in the presence of Cd. The binding activity of GATA-2 was not affected by Cd. This study showed that Cd inhibited HIF-1 binding activity and Epo promoter activity, and then suppressed Epo protein production. Inhibition of Epo gene expression by Cd depends on suppression of HIF-1 binding activity, not on alteration of GATA function.

Original languageEnglish
Pages (from-to)267-273
Number of pages7
JournalArchives of Toxicology
Issue number5
Publication statusPublished - 2003 May 1
Externally publishedYes


  • Cadmium
  • Erythropoietin
  • GATA
  • Hypoxia-inducible factor 1α
  • Transcriptional regulation

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis


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