Differential roles for Nrf2 and AP-1 in upregulation of HO-1 expression by arsenite in murine embryonic fibroblasts.
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.
Harada
Harumi
H
Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
Sugimoto
Rika
R
Watanabe
Ayaka
A
Taketani
Shigeru
S
Okada
Kosuke
K
Warabi
Eiji
E
Siow
Richard
R
Itoh
Ken
K
Yamamoto
Masayuki
M
Ishii
Tetsuro
T
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D018053:Arsenites / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D019833:Genistein / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism
D000873:Anthracenes; D018053:Arsenites; D004791:Enzyme Inhibitors; D051267:NF-E2-Related Factor 2; D013778:Tetrazolium Salts; D013844:Thiazoles; D018808:Transcription Factor AP-1; C432165:pyrazolanthrone; D019833:Genistein; D051547:Heme Oxygenase-1; D019061:src-Family Kinases; C022616:thiazolyl blue; C015001:arsenite