Abstract
The molecular mechanisms underlying Hodgkin's disease remain obscure, but it has been recognized that the neoplastic cells display high levels of constitutively active nuclear NF-κB. Here we demonstrate that although nuclear NF-κB is transcriptionally active, the Hodgkin cells fail to activate NF-κB dependent transcription in response to CD40 ligand. In three Hodgkin cell lines examined each had abnormalities in expression of IκBα which could account for the deregulated NF-κB. Although all three cell lines had greater than normal levels of IκBα mRNA no IκBα protein could be detected in the KM-H2 cells, while the L428 cell line contains a C-terminally truncated IκBα species that fails to associate with NF-κB. The HDLM-2 cell line contains a more slowly migrating form of IκBα that can associate with NF-κB, but increasing the level of this protein within the cell fails to inhibit nuclear NF-κB. Addition of recombinant IκBα to nuclear extracts from all three cell lines resulted in complete inhibition of NF-κB DNA binding activity and introduction of a plasmid expressing IκBα into the cells inhibited the transcriptional activity of an NF-κB dependent reporter plasmid. Thus the constitutive expression of NF-κB in Hodgkin cells is a direct consequence of the abnormal expression of IκBα rather than changes in NF-κB that render it refractory to inhibition by IκB proteins. These changes could, at least in part, account for the characteristic activated phenotype of Hodgkin cells and their pattern of cytokine secretion, which determine the pathological appearance and clinical manifestations of Hodgkin's disease.
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Wood, K., Roff, M. & Hay, R. Defective IκBα in Hodgkin cell lines with constitutively active NF-κB. Oncogene 16, 2131–2139 (1998). https://doi.org/10.1038/sj.onc.1201735
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DOI: https://doi.org/10.1038/sj.onc.1201735
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