Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Hydrogen peroxide-induced apoptosis is CD95-independent, requires the release of mitochondria-derived reactive oxygen species and the activation of NF-κB

Oncogene volume 18, pages 747–757 (1999)Cite this article

Abstract

Reactive oxygen species (ROS) play an important role in cell death induced by many different stimuli. This study shows that hydrogen peroxide-induced apoptosis in T-cells did not require tyrosine kinase p56lck, phosphatase CD45, the CD95 receptor and its associated Caspase-8. H2O2-triggered cell death led to the induced cleavage and activation of Caspase-3. Hydrogen peroxide-treatment of T-cells resulted in the formation of mitochondrial permeability transition pores, a rapid decrease of the mitochondrial transmembrane potential ΔΨm and the release of Cytochrome C. Inhibition of the mitochondrial permeability transition by bongkrekic acid (BA), or interference with the mitochondrial electron transport system by rotenone or menadione prevented the cytotoxic effect of H2O2. Antimycin A, a mitochondrial inhibitor that increases the release of mitochondrial ROS (MiROS), enhanced apoptosis. Overexpression of Bcl-2 and the viral anti-apoptotic proteins BHRF-1 and E1B 19K counteracted H2O2-induced apoptosis. Pharmacological and genetic inhibition of transcription factor NF-κB protected cells from hydrogen peroxide-elicited cell death. This detrimental effect of NF-κB mediating hydrogen peroxide-induced cell death presumably relies on the induced expression of death effector genes such as p53, which was NF-κB-dependently upregulated in the presence of H2O2.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Abbadie C, Kabrun N, Bouali F, Smardova J, Stehelin D, Vandenbunder B and Enrietto PJ. . 1993 Cell 75: 899–912.

  • Baeuerle PA, Rupec R and Pahl HL. . 1995 Path. Biol. 44: 29–35.

  • Baldwin AS. . 1996 Annu. Rev. Immunol. 14: 649–683.

  • Bauer MKA, Vogt M, Los M, Siegel J, Wesselborg S and Schulze-Osthoff K. . 1998 J. Biol. Chem. 273: 8048–8055.

  • del Carmen Ruiz-Ruiz M, Izquierdo M, de Murcia G and López-Rivas A. . 1997 Eur. J. Immunol. 27: 1442–1450.

  • Clemens JA, Stephenson DT, Smalstig EB, Dixon EP and Little SP. . 1997 Stroke 28: 1073–1080.

  • Clement MV and Stamenkovic I. . 1996 EMBO J. 15: 216–225.

  • Dröge W and Holm E. . 1997 FASEB J. 11: 1077–1089.

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

  • Eischen CM, Dick CJ and Leibson PJ. . 1994 J. Immunol. 153: 1947–1954.

  • Farrow SN and Brown R. . 1996 Curr. Opin. Genet. Dev. 6: 45–49.

  • Galter D, Mihm S and Dröge W. . 1994 Eur. J. Biochem. 221: 639–648.

  • Griffith OW and Meister A. . 1979 J. Biol. Chem. 254: 7558–7560.

  • Grilli M, Pizzi M, Memo M and Spano P. . 1996 Science 274: 1383–1385.

  • Grimm S, Bauer MK, Baeuerle PA and Schulze-Osthoff K. . 1996 J. Cell Biol. 134: 13–23.

  • Han J, Sabbatini P and White E. . 1996 Mol. Cell Biol. 16: 5857–5864.

  • Hehner SP, Heinrich M, Bork PM, Vogt M, Ratter F, Lehmann V, Schulze-Osthoff K, Dröge W and Schmitz ML. . 1998 J. Biol. Chem. 273: 1288–1298.

  • Hengartner MO and Horvitz HR. . 1994 Cell 76: 665–676.

  • Hermeking H and Eick D. . 1994 Science 265: 2091–2093.

  • Hoyt KR, Gallagher AJ, Hastings TG and Reynolds IJ. . 1997 Neurochem. Res. 22: 333–340.

  • Hug H, Enari M and Nagata S. . 1994 FEBS Lett. 351: 311–313.

  • Hug H, Strand S, Grambihler A, Galle J, Hack V, Stremmel W, Krammer PH and Galle PR. . 1997 J. Biol. Chem. 272: 28191–28193.

  • Hurley TR, Hyman R and Sefton BM. . 1993 Mol. Cell Biol. 13: 1651–1656.

  • Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ, Fearon ER, Sundaresan M, Finkel T and Goldschmidt-Clermont PJ. . 1997 Science 275: 1649–1652.

  • Khanim F, Dawson C, Meseda CA, Dawson J, Mackett M and Young LS. . 1997 J. Gen. Virol. 78: 2987–2999.

  • Knebel A, Rahmsdorf HJ, Ullrich A and Herrlich P. . 1996 EMBO J. 15: 5314–5325.

  • Konishi H, Tanaka M, Takemura Y, Matsuzaki H, Ono Y, Kikkawa Y and Nishizuka Y. . 1997 Proc. Natl. Acad. Sci. USA 94: 11233–11237.

  • Kroemer G, Zamzami N and Susin SA. . 1997 Immunol. Today 18: 44–51.

  • Limbourg FP, Städtler H, Chinnadurai G, Baeuerle PA and Schmitz ML. . 1996 J. Biol. Chem. 271: 20392–20398.

  • Lin KI, Lee SH, Narayanan R, Baraban JM, Hardwick JM and Ratan RR. . 1995 J. Cell Biol. 131: 1149–1161.

  • Los M, Schenk H, Hexel K, Baeuerle PA, Dröge W and Schulze-Osthoff K. . 1995 EMBO J. 14: 3731–3740.

  • Macho A, Hirsch T, Marzo I, Marchetti P, Dallaporta B, Susin SA, Zamzami N and Kroemer G. . 1997 J. Immunol. 158: 4612–4619.

  • Mancini M, Anderson BO, Caldwell E, Sedghinasab M, Paty PB and Hockenbery DM. . 1997 J. Cell Biol. 138: 449–469.

  • Marchetti P, Castedo M, Susin SA, Zamzami N, Hirsch T, Macho A, Haeffner A, Hirsch F, Geuskens M and Kroemer G. . 1996 J. Exp. Med. 184: 1155–1160.

  • Meyer M, Schreck R and Baeuerle PA. . 1993 EMBO J. 12: 2005–2015.

  • Mollereau B, Blanchard D, Deas O, Dumont C, Metivier D, Bernard A, McGrew JT, Charpentier B, Vazquez A and Senik A. . 1997 J. Immunol. 159: 2668–2677.

  • Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Schevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME and Dixit VM. . 1996 Cell 85: 817–827.

  • Nakamura H, Nakamura K and Yodoi J. . 1997 Annu. Rev. Immunol. 15: 351–369.

  • Nicoletti I, Migliorati G, Pagliacci MC, Grignani F and Riccardi C. . 1991 J. Immunol. Methods 139: 271–279.

  • Polyak K, Xia Y, Zweier JL, Kinzler KW and Vogelstein B. . 1997 Nature 389: 300–305.

  • Qin ZH, Wang Y, Nakai M and Chase TN. . 1998 Mol. Pharmacol. 53: 33–42.

  • Rao L, Debbas M, Sabbatini P, Hockenbery D, Korsmeyer S and White E. . 1992 Proc. Natl. Acad. Sci. USA 89: 7742–7746.

  • Salvesen GS and Dixit VM. . 1997 Cell 91: 443–446.

  • Sakahira H, Enari M and Nagata S. . 1998 Nature 391: 96–99.

  • Scaffidi C, Medema JP, Krammer PH and Peter ME. . 1997 J. Biol. Chem. 272: 26953–26958.

  • Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin K-M, Krammer PH and Peter ME. . 1998 EMBO J. 17: 1675–1687.

  • Schmitz ML, Indorf A, Limbourg FP, Staedtler H, Traenckner EB and Baeuerle PA. . 1996 Mol. Cell Biol. 16: 4052–4063.

  • Schraven B and Peter ME. . 1995 FEBS Lett. 368: 491–494.

  • Schreck R, Rieber P and Baeuerle PA. . 1991 EMBO J. 10: 2247–2258.

  • Sies H. . 1993 Eur. J. Biochem. 215: 213–219.

  • Sha W. . 1998 J. Exp. Med. 187, 143–146.

  • Slater AF, Stefan C, Novel I, van den Dobbelsteen DJ and Orrenius S. . 1995 Toxicol. Lett. 82–83: 149–153.

  • Subramanian T, Tarodi B, Govindarajan R, Boyd JM, Yoshida K and Chinnadurai G. . 1993 Gene 124: 173–181.

  • Sulciner DJ, Irani K, Yu ZX, Ferrans VJ, Goldschmidt-Clermont P and Finkel T. . 1996 Mol. Cell Biol. 16: 7115–7121.

  • Traenckner EB, Pahl HL, Henkel T, Schmidt KN, Wilk S and Baeuerle PA. . 1995 EMBO J. 14: 2876–2883.

  • Van Antwerp D, Martin SJ, Verma IM and Green DR. . 1998 Trends Cell Biol. 8: 107–111.

  • Villa P, Kaufmann SH and Earnshaw WC. . 1997 Trends. Biochem. Sci. 22: 388–393.

  • Wautier JL, Wautier MP, Schmidt AM, Anderson GM, Hori O, Zoukourian C, Capron L, Chappey O, Yan SD, Brett J et al. . 1994 Proc. Natl. Acad. Sci. USA 91: 7742–7746.

  • White E and Cipriani R. . 1990 Mol. Cell Biol. 10: 120–130.

  • Wu H and Lozano G. . 1994 J. Biol. Chem. 269: 20067–20074.

  • Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng T-I, Jones DP and Wang X. . 1997 Science 275: 1129–1132.

  • Yousefi S, Green DR, Blaser K and Simon HU. . 1994 Proc. Natl. Acad. Sci. USA 91: 10868–10872.

  • Zamzami N, Susin SA, Marchetti P, Hirsch T, Gomez Monterrey I, Castedo M and Kroemer G. . 1996 J. Exp. Med. 183: 1533–1544.

Download references

Acknowledgements

This work was supported by a European Biomed-2 grant (to MLS) and the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israeli's Ministry of Science (to SPH). We thank Dr Duine (Delft, Netherlands) for kindly providing bongkrekic acid and Dr Burkhart Schraven (Heidelberg) for the Jurkat p56lck− and CD45− cells. We are grateful to Dr Marcus E Peter (DKFZ, Heidelberg) for a Bcl-2 overexpressing Jurkat cell line, Jurkat CD95− cells and antibodies recognizing CD95 (α-APO-1) and Caspase-8 as well as to Dr A Bürkle (DKFZ, Heidelberg) for α-PARP antibodies.

Author information

Author notes

  1. Andreas Dumont and Steffen P Hehner: A Dumont and SP Hehner contributed equally to this paper

Authors and Affiliations

  1. Department of Immunochemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Andreas Dumont, Steffen P Hehner, Thomas G Hofmann, Wulf Dröge & M Lienhard Schmitz

  2. Molecular Eye Genetics Group, Ludwig-Maximilians-University, Munich, Germany

    Marius Ueffing

Authors
  1. Andreas Dumont
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steffen P Hehner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas G Hofmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marius Ueffing
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wulf Dröge
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Lienhard Schmitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dumont, A., Hehner, S., Hofmann, T. et al. Hydrogen peroxide-induced apoptosis is CD95-independent, requires the release of mitochondria-derived reactive oxygen species and the activation of NF-κB. Oncogene 18, 747–757 (1999). https://doi.org/10.1038/sj.onc.1202325

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202325

Keywords

This article is cited by

Search

Advanced search

Quick links