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Differential effects of NF-κB on apoptosis induced by DNA-damaging agents: the type of DNA damage determines the final outcome

Oncogene volume 25, pages 6239–6251 (2006)Cite this article

Abstract

The transcription factor nuclear factor kappa-B (NF-κB) is generally regarded as an antiapoptotic factor. Accordingly, NF-κB activation inhibits death ligand-induced apoptosis. In contrast, ultraviolet light B (UVB)-induced apoptosis is not inhibited but even enhanced upon NF-κB activation by interleukin-1 (IL-1). This study was performed to identify the molecular mechanisms underlying this switch of NF-κB. Enhancement of UVB-induced apoptosis was always associated with increased release of tumour necrosis factor-α (TNF-α), which was dependent on NF-κB activation. The same was observed when UVA and cisplatin were used, which like UVB induce base modifications. In contrast, apoptosis caused by DNA strand breaks was not enhanced by IL-1, indicating that the type of DNA damage is critical for switching the effect of NF-κB on apoptosis. Surprisingly, activated NF-κB induced TNF-α mRNA expression in the presence of all DNA damage-inducing agents. However, in the presence of DNA strand breaks, there was no release of the TNF-α protein, which is so crucial for enhancing apoptosis. Together, this indicates that induction of DNA damage may have a significant impact on biological effects but it is the type of DNA damage that determines the final outcome. This may have implications for the role of NF-κB in carcinogenesis and for the application of NF-κB inhibitors in anticancer therapy.

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Abbreviations

IκBα:

inhibitor of kappa-B

IKK:

IκB kinase

IL-1:

interleukin-1

NF-κB:

nuclear factor kappa-B

TNF-α:

tumor necrosis factor-α

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Acknowledgements

We are greatful to P Scheurich, Institue of Cellbiology and Immunology, University of Stuttgart, for generous supply of FACS antibodies and antagonistic anti-TNF-R1 Fab. We thank N Peters, University of Stuttgart for exellent technical support and H Grothuesmann, University of Münster, for assistance with γ-irradiation of cells. This work was funded by the German Research Foundation, SFB 415/A16, The Federal Ministry of Environmental Protection St.Sch_4491 and the Ceries Award 2004 to TS.

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Authors and Affiliations

  1. Department of Dermatology, University of Muenster, Muenster, Germany

    E Strozyk & B Pöppelmann

  2. Department of Dermatology, University of Kiel, Kiel, Germany

    T Schwarz

  3. Department of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany

    D Kulms

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  1. E Strozyk
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  2. B Pöppelmann
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Correspondence to D Kulms.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Strozyk, E., Pöppelmann, B., Schwarz, T. et al. Differential effects of NF-κB on apoptosis induced by DNA-damaging agents: the type of DNA damage determines the final outcome. Oncogene 25, 6239–6251 (2006). https://doi.org/10.1038/sj.onc.1209655

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