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Thioredoxin-dependent redox regulation of the antioxidant responsive element (ARE) in electrophile response

Oncogene volume 22, pages 1860–1865 (2003)Cite this article

Abstract

Thioredoxin is a redox-regulating protein, the expression of which is induced by various forms of oxidative stress. Thioredoxin controls the interactions of various transcription factors through redox regulation. In K562 cells, we have previously reported that hemin induces activation of the thioredoxin gene by regulating NF-E2-related factor (Nrf2) through the antioxidant responsive element (ARE). We showed here that tert-butylhydroquinone (tBHQ), an electrophile stressor, activates the thioredoxin gene through the ARE. In an electrophoretic mobility shift assay, a specific Nrf2/small Maf binding complex was induced by tBHQ and bound to the ARE. Overexpression of Nrf2 increased the tBHQ-induced thioredoxin gene activation through the ARE, whereas that of Jun and Fos suppressed the activation. The tBHQ-induced ARE binding activity was completely abrogated by an oxidizing agent, diamide, whereas 2-mercaptoethanol (2-ME) reversibly recovered the inhibitory effects of diamide, suggesting that ARE binding activity is redox-dependent. Moreover, overexpression of thioredoxin enhanced the ARE-mediated thioredoxin gene activation by tBHQ. Therefore, ARE-mediated induction of thioredoxin expression is a mechanism of enhancing signal transduction through the ARE in electrophile-induced stress responses.

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Acknowledgements

We thank Ms Y Kanekiyo for secretarial help. We thank Dr K Itoh and Dr M Yamamoto for providing pEF-Nrf2, pEF-MafK vectors and anti-MafK antibodies. We also thank Dr Y Nakabeppu for pYN3215, pYN3215/c-Jun and pYN3215/c-Fos vectors. This study was supported by a grant-in-aid for Research and Development Program for New Bio-Industry Initiatives and by a grant-in-aid for Scientific Research from the Ministry of Education, Science and Culture, Japan. Yong-Chul Kim was a recipient of the New Energy and Industrial Technology Development Organization (NEDO) Junior Research Fellowship and is a recipient of the Research Fellowship of the Japan Society for the Promotion of Science (JSPS).

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Authors and Affiliations

  1. Department of Biological Responses, Institute for Virus Research, Kyoto University, 53 Shogoin, Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan

    Yong-Chul Kim, Norihiko Kondo, Hiroshi Masutani & Junji Yodoi

  2. Biomedical Special Research Unit, Human Stress Signal Research Center, National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31 Midorigaoka, Ikeda, Osaka, 563-8577, Japan

    Yoshimi Yamaguchi, Hiroshi Masutani & Junji Yodoi

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  1. Yong-Chul Kim
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Correspondence to Hiroshi Masutani.

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Kim, YC., Yamaguchi, Y., Kondo, N. et al. Thioredoxin-dependent redox regulation of the antioxidant responsive element (ARE) in electrophile response. Oncogene 22, 1860–1865 (2003). https://doi.org/10.1038/sj.onc.1206369

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