Differential roles for Nrf2 and AP-1 in upregulation of HO-1 expression by arsenite in murine embryonic fibroblasts

Harumi Harada, Rika Sugimoto, Ayaka Watanabe, Shigeru Taketani, Kosuke Okada, Eiji Warabi, Richard Siow, Ken Itoh, Masayuki Yamamoto, Tetsuro Ishii

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

Abstract

Heme oxygenase-1 (HO-1) is markedly upregulated by sodium arsenite and previous studies implicated the transcriptional enhancers Nrf2 and AP-1 in arsenite-induced ho-1 gene expression in murine cells. To further evaluate the role of Nrf2 and its signalling pathway in the induction of HO-1 in response to low levels of arsenite, this paper studied wild-type and Nrf2-deficient murine embryonic fibroblasts. It was found that Nrf2 plays a crucial role in the early activation of ho-1 transcription and that increased Nrf2 levels returned to basal levels within 24 h. In Nrf2-/- cells, ho-1 gene activation increased gradually and HO-1 protein levels were approximately half of those attained in Nrf2+/+ cells. The tyrosine kinase inhibitor genistein and JNK inhibitor SP600125 significantly attenuated arsenite induced increases in ho-1 mRNA levels in Nrf2 deficient cells but had negligible effects on Nrf2 activation, suggesting tyrosine kinase/JNK/c-Jun plays a key role in the HO-1 upregulation via AP-1.

Original languageEnglish
Pages (from-to)297-304
Number of pages8
JournalFree Radical Research
Volume42
Issue number4
DOIs
Publication statusPublished - 2008
Externally publishedYes

Keywords

  • AP-1
  • Arsenite
  • Genistein
  • Heme oxygenase-1
  • JNK
  • Nrf2
  • PD153035
  • Src

ASJC Scopus subject areas

  • Biochemistry

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