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

doi:10.1080/10715760801975735

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 journal › Article › peer-review

36 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 language	English
Pages (from-to)	297-304
Number of pages	8
Journal	Free Radical Research
Volume	42
Issue number	4
DOIs	https://doi.org/10.1080/10715760801975735
Publication status	Published - 2008
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Biochemistry

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10.1080/10715760801975735

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

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.",

keywords = "AP-1, Arsenite, Genistein, Heme oxygenase-1, JNK, Nrf2, PD153035, Src",

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

note = "Funding Information: We thank Professor Giovanni E. Mann, Professor Yoshito Kumagai and Dr Baojie Li for their encouragement during this study. This study was supported by grants from the Japan Society for the Promotion of Science (TI) and the British Heart Foundation (RCMS).",

year = "2008",

doi = "10.1080/10715760801975735",

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volume = "42",

pages = "297--304",

journal = "Free Radical Research",

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T1 - Differential roles for Nrf2 and AP-1 in upregulation of HO-1 expression by arsenite in murine embryonic fibroblasts

AU - Harada, Harumi

AU - Sugimoto, Rika

AU - Watanabe, Ayaka

AU - Taketani, Shigeru

AU - Okada, Kosuke

AU - Warabi, Eiji

AU - Siow, Richard

AU - Itoh, Ken

AU - Yamamoto, Masayuki

AU - Ishii, Tetsuro

N1 - Funding Information: We thank Professor Giovanni E. Mann, Professor Yoshito Kumagai and Dr Baojie Li for their encouragement during this study. This study was supported by grants from the Japan Society for the Promotion of Science (TI) and the British Heart Foundation (RCMS).

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

KW - AP-1

KW - Arsenite

KW - Genistein

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KW - JNK

KW - Nrf2

KW - PD153035

KW - Src

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

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