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Molecular mechanisms of constitutive NF-κB/Rel activation in Hodgkin/Reed-Sternberg cells

Oncogene volume 18, pages 943–953 (1999)Cite this article

Abstract

A common characteristic of malignant cells derived from patients with Hodgkin's disease (HD) is a high level of constitutive nuclear NF-κB/Rel activity, which stimulates proliferation and confers resistance to apoptosis. We have analysed the mechanisms that account for NF-κB activation in a panel of Hodgkin/Reed-Sternberg (H-RS) cell lines. Whereas two cell lines (L428 and KMH-2) expressed inactive IκBα, no significant changes in NF-κB or IκB expression were seen in other H-RS cells (L591, L1236 and HDLM-2). Constitutive NF-κB was susceptible to inhibition by recombinant IκBα, suggesting that neither mutations in the NF-κB genes nor posttranslational modifications of NF-κB were involved. Endogenous IκBα was bound to p65 and displayed a very short half-life. IκBα degradation could be blocked by inhibitors of the NF-κB activating pathway. Proteasomal inhibition caused an accumulation of phosphorylated IκBα and a reduction of NF-κB activity in HDLM-2 and L1236 cells. By in vitro kinase assays we demonstrate constitutive IκB kinase (IKK) activity in H-RS cells, indicating ongoing signal transduction. Furthermore, H-RS cells secrete one or more factor(s) that were able to trigger NF-κB activation. We conclude that aberrant activation of IKK's, and in some cases defective IκBs, lead to constitutive nuclear NF-κB activity, which in turn results in a growth advantage of Hodgkin's disease tumor cells.

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Acknowledgements

We thank Rudolf Dettmer for providing us with highly purified recombinant IκBα protein.

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Authors and Affiliations

  1. Max-Delbrück-Centrum for Molecular Medicine, Robert-Rössle-Str. 10, Berlin, D-13122, Germany

    Daniel Krappmann, Florian Emmerich, Uwe Kordes, Erika Scharschmidt, Bernd Dörken & Claus Scheidereit

  2. Humboldt University of Berlin, Universitätsklinikum Charité, Robert-Rössle-Klinik, Berlin, D-13122, Germany

    Florian Emmerich & Bernd Dörken

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Krappmann, D., Emmerich, F., Kordes, U. et al. Molecular mechanisms of constitutive NF-κB/Rel activation in Hodgkin/Reed-Sternberg cells. Oncogene 18, 943–953 (1999). https://doi.org/10.1038/sj.onc.1202351

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