Skip to main content
SpringerLink
Log in

Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels

  • Short Report
  • Published:
Oncogene Submit manuscript

Abstract

Nrf2 is a basic leucine zipper transcriptional activator that is essential for the coordinate transcriptional induction of various antioxidant drug-metabolizing enzymes. Numerous studies have firmly established Nrf2's importance in protection from oxidative stress and certain chemical insults. Given the protective function of Nrf2, surprisingly few studies have focused on the relationship between Nrf2 and apoptosis. Therefore, we analysed how Nrf2 influences Fas signaling using Nrf2-deficient T cells. At a concentration of 1 μg/ml, the anti-Fas antibody induced 60% of cell death in Nrf2-deficient cultured thymocytes while, using the same treatment, only 40% of Nrf2 wild-type thymocytes died (P<0.05). Nrf2 deficiency enhances the sensitivity of Fas-mediated apoptosis in T cells. Next we examined the effect of Nrf2 deficiency during hepatocellular apoptosis in vivo. In comparison to wild-type mice, Nrf2-deficient mice displayed more severe hepatitis after induction with the anti-Fas antibody or tumor necrosis factor (TNF)-α. The enhanced sensitivity to anti-Fas or TNF-α stimulation was restored by preadministration of glutathione ethyl monoester, a compound capable of passing the cell membrane and upregulating the intracellular levels of glutathione. The results indicated that Nrf2 activity regulates the sensitivity of death signals by means of intracellular glutathione levels.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2

Similar content being viewed by others

References

  • Anderson ME . (1997). Adv. Pharmacol., 38, 65–78.

  • Chan JY and Kwong M . (2000). Biochim. Biophys. Acta, 1517, 19–26.

  • Chan K, Han XD and Kan YW . (2001). Proc. Natl. Acad. Sci. USA, 98, 4611–4616.

  • Chen TS, Richie JP, Nagasawa HT and Lang CA . (2001). Mech. Ageing Dev., 120, 127–139.

  • Chiba T, Takahashi S, Sato N, Ishii S and Kikuchi K . (1996). Eur. J. Immunol., 26, 1164–1169.

  • Cho HY, Jedlicka AE, Reddy SP, Kensler TW, Yamamoto M, Zhang LY and Kleeberger SR . (2002). Am. J. Respir. Cell Mol. Biol., 26, 175–182.

  • Colell A, Garcia-Ruiz C, Miranda M, Ardite E, Mari M, Morales A, Corrales F, Kaplowitz N and Fernandez-Checa JC . (1998). Gastroenterology, 115, 1541–1551.

  • Droge W, Schulze-Osthoff K, Mihm S, Galter D, Schenk H, Eck HP, Roth S and Gmunder H . (1994). FASEB J., 8, 1131–1138.

  • Enomoto A, Itoh K, Nagayoshi E, Haruta J, Kimura T, O'Connor T, Harada T and Yamamoto M . (2001). Toxicol. Sci., 59, 169–177.

  • Favreau LV and Pickett CB . (1991). J. Biol. Chem., 266, 4556–4561.

  • Galle PR, Hofmann WJ, Walczak H, Schaller H, Otto G, Stremmel W, Krammer PH and Runkel L . (1995). J. Exp. Med., 182, 1223–1230.

  • Hall AG . (1999). Eur. J. Clin. Invest., 29, 238–245.

  • Haouzi D, Lekehal M, Tinel M, Vadrot N, Caussanel L, Letteron P, Moreau A, Feldmann G, Fau D and Pessayre D . (2001). Hepatology, 33, 1181–1188.

  • Hentze H, Gantner F, Kolb SA and Wendel A . (2000). Am. J. Pathol., 156, 2045–2056.

  • Hentze H, Kunstle G, Volbracht C, Ertel W and Wendel A . (1999). Hepatology, 30, 177–185.

  • Hirata H, Takahashi A, Kobayashi S, Yonehara S, Sawai H, Okazaki T, Yamamoto K and Sasada M . (1998). J. Exp. Med., 187, 587–600.

  • Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S and Yamamoto M . (2000). J. Biol. Chem., 275, 16023–16029.

  • Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M and Nabeshima Y . (1997). Biochem. Biophys. Res. Commun., 236, 313–322.

  • Itoh K, Igarashi K, Hayashi N, Nishizawa M and Yamamoto M . (1995). Mol. Cell. Biol., 15, 4184–4193.

  • Itoh K, Ishii T, Wakabayashi N and Yamamoto M . (1999). Free Radic. Res., 31, 319–324.

  • Jones TW, Thor H and Orrenius S . (1986). Arch. Toxicol., 9 (Suppl.), 259–271.

  • Kotlo KU, Yehiely F, Efimova E, Harasty H, Hesabi B, Shchors K, Einat P, Rozen A, Berent E and Deiss LP . (2003). Oncogene, 22, 797–806.

  • Leist M, Gantner F, Kunstle G, Bohlinger I, Tiegs G, Bluethmann H and Wendel A . (1996). Mol. Med., 2, 109–124.

  • Medema JP, Scaffidi C, Kischkel FC, Shevchenko A, Mann M, Krammer PH and Peter ME . (1997). EMBO J., 16, 2794–2804.

  • Meister A . (1992). Biochem. Pharmacol., 44, 1905–1915.

  • Moi P, Chan K, Asunis I, Cao A and Kan YW . (1994). Proc. Natl. Acad. Sci. USA, 91, 9926–9930.

  • Nagata S . (1997). Cell, 88, 355–365.

  • Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, Itoh N, Suda T and Nagata S . (1993). Nature, 364, 806–809.

  • Prestera T, Talalay P, Alam J, Ahn YI, Lee PJ and Choi AM . (1995). Mol. Med., 1, 827–837.

  • Rahman I, Mulier B, Gilmour PS, Watchorn T, Donaldson K, Jeffery PK and MacNee W . (2001). Biochem. Pharmacol., 62, 787–794.

  • Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P and Kensler TW . (2001). Proc. Natl. Acad. Sci. USA, 98, 3410–3415.

  • Rushmore TH, King RG, Paulson KE and Pickett CB . (1990). Proc. Natl. Acad. Sci. USA, 87, 3826–3830.

  • Srivastava SK, Xia H, Pal A, Hu X, Guo J and Singh SV . (2000). Cancer Lett., 153, 35–39.

  • Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S and Peter ME . (1998). Eur. J. Biochem., 254, 439–459.

  • Thronberry NA and Lazebnik Y . (1998). Science, 281, 1312–1316.

  • Uhlig S and Wendel A . (1992). Life Sci., 51, 1083–1094.

  • Widmann C, Gibson S and Johnson GL . (1998). J. Biol. Chem., 273, 7141–7147.

  • Xu Y, Jones BE, Neufeld DS and Czaja MJ . (1998). Gastroenterology, 115, 1229–1237.

  • Yoh K, Itoh K, Enomoto A, Hirayama A, Yamaguchi N, Kobayashi M, Morito N, Koyama A, Yamamoto M and Takahashi S . (2001). Kidney Int., 60, 1343–1353.

  • Zhivotovsky B, Burgess DH, Vanags D M and Orrenius S . (1997). Biochem. Biophys. Res. Commun., 230, 481–488.

Download references

Acknowledgements

This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports and Culture, the Japanese Society for Promotion of Sciences (RFTF), Core Research for Evolutional Sciences and Technology (CREST), and Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN). We thank Vincent Kelly (Banyu Pharmaceutical Co., Ltd) for their help and discussion and N Kaneko (University of Tsukuba) for their excellent assistance.

Author information

Authors and Affiliations

  1. Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Naoki Morito, Ken Itoh, Masayuki Yamamoto & Satoru Takahashi

  2. Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Keigyou Yoh, Aki Hirayama & Akio Koyama

  3. Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Ken Itoh & Masayuki Yamamoto

  4. Laboratory Animal Resource Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Satoru Takahashi

Authors
  1. Naoki Morito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keigyou Yoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ken Itoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aki Hirayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akio Koyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masayuki Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Satoru Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Satoru Takahashi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morito, N., Yoh, K., Itoh, K. et al. Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels. Oncogene 22, 9275–9281 (2003). https://doi.org/10.1038/sj.onc.1207024

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207024

  • Springer Nature Limited

Keywords

This article is cited by

Search

Navigation