Abstract
The latent membrane protein 1 (LMP1) oncogene of Epstein-Barr virus (EBV) is selectively expressed in the Reed-Sternberg (RS) cells of EBV-associated Hodgkin's disease (HD). However, no differences in clinical presentation and course are found between EBV positive and EBV negative forms of HD suggesting a common pathogenetic mechanism. We have studied the LMP1 associated signaling pathways and their dominant negative inhibition in the myelomonocytic HD-MyZ and the B-lymphoid L-428 HD cell lines. In both EBV negative cell lines expression of LMP1 is associated with the formation of multinuclear RS cells. Dominant negative inhibition of NF-κB mediated signaling at the step of IκB-α phosphorylation results in increased cell death with only a few typical RS cells resistant to overexpression of the dominant negative inhibitor IκB-α-NΔ54. However, dominant negative inhibition of NF-κB mediated signaling at the early step of TRAF2 interaction results in the formation of multinuclear cells in both cell lines and, in addition, in clusters of small mononuclear cells in the HD-MyZ cell line. In HD-MyZ cells overexpression of the powerful JBD-inhibitor of the JNK signal transduction pathway is restricted to small cells and never observed in RS cells. These small cells undergo apoptosis as shown by the TUNEL technique. Apoptosis of small cells is still observed after co-transfection of JBD and LMP1 but in addition a few apoptotic HD-MyZ cells with large fused nuclear masses are identified suggesting that specific inhibition of JNK leads also to apoptosis of LMP1 induced RS cells. Thus, activation of the JNK signaling pathway is also important in the formation of Reed-Sternberg cells. Our findings are consistent with a model where all three LMP1 associated functions, i.e. NF-κB mediated transcription, TRAF2 dependent signaling, and c-Jun activation act as a common pathogenetic denominator of both EBV negative and EBV positive HD.
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Acknowledgements
The plasmids encoding full length human TRAF2, (pcDNA3-TRAF2), and an HA-tagged, human TRAF2 deletion mutant lacking amino acids 1 – 97, (pcDNA3HA-TRAF2-NΔ97), which acts as a dominant negative inhibitor of TRAF2-mediated NF-κB activation, were a kind gift from David V Goeddel, Tularik Inc. (San Francisco, CA, USA). The plasmid encoding MKK4, (pcDNA3-Flag-MKK4), the dominant negative MKK4 expresion vector pcDNA3-Flag-MKK4 (Ala), whose phosphorylation sites Ser257 and Thr261 have been replaced by Ala residues, and the plasmid pcDNA3-Flag-JBD, expressing the JNK binding domain (residues 127 – 281) of the JNK interacting protein-1 (JIP-1), were a kind gift from Roger Davis (HHMI, Worcester, MA, USA). The authors thank Phyllis Spatrick and Barbara Eddy for vector amplification and sequencing as well as Suzanne King for skilful secretarial assistance in assembling the manuscript. C Berger is a pediatric postdoctoral research fellow supported by the Swiss National Science Foundation. S Rothenberger is supported by the Schweizerische Krebsliga.
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Knecht, H., Berger, C., McQuain, C. et al. Latent membrane protein 1 associated signaling pathways are important in tumor cells of Epstein-Barr virus negative Hodgkin's disease. Oncogene 18, 7161–7167 (1999). https://doi.org/10.1038/sj.onc.1203177
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DOI: https://doi.org/10.1038/sj.onc.1203177
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