The human B-cell lymphoma cell line RC-K8 has multiple genetic alterations that dysregulate the Rel/NF-κB signal transduction pathway
- 12 December 2002
- journal article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 21 (57), 8759-8768
- https://doi.org/10.1038/sj.onc.1206033
Abstract
The human large B-cell lymphoma cell line RC-K8 has a rearranged REL locus that directs the production of a chimeric protein, termed REL-NRG (Non-Rel Gene). In this study, we show that RC-K8 cells have constitutively nuclear heterodimeric and homodimeric DNA-binding complexes that consist of p50, REL, and REL-NRG. In vitro, IkappaBalpha can block the DNA-binding activity of wild-type REL homodimers but not REL-NRG homodimers. In vivo, REL-NRG cannot activate transcription of a kappaB site reporter plasmid, suggesting that it is a transcription repressing or blocking REL protein. By Western blotting, no IkappaBalpha protein can be detected in extracts of RC-K8 cells. The absence of IkappaBalpha protein in RC-K8 cells appears to be due to mutations that cause premature termination of translation in three of the four copies of the IKBA gene in RC-K8 cells. Re-expression of wild-type IkappaBalpha or a super-repressor form of IkappaBalpha in RC-K8 cells is cytotoxic; in contrast, expression of a dominant-negative form of IkappaB kinase does not affect the growth of RC-K8 cells. By cDNA microarray analysis, a number of previously identified Rel/NF-kappaB target genes are overexpressed in RC-K8 cells, consistent with there being transcriptionally active REL complexes. Taken together, our results suggest that the growth of RC-K8 cells is dependent on the activity of nuclear wild-type REL dimers, while the contribution of REL-NRG to the transformed state of RC-K8 cells is less clear. Nevertheless, the RC-K8 cell line is the first tumor cell line identified with mutations in genes encoding multiple proteins in the Rel/NF-kappaB signal transduction pathway.Keywords
This publication has 38 references indexed in Scilit:
- Rel/NF-κB/IκB signal transduction in the generation and treatment of human cancerCancer Letters, 2002
- Similar patterns of genomic alterations characterize primary mediastinal large-B-cell lymphoma and diffuse large-B-cell lymphomaGenes, Chromosomes and Cancer, 2002
- IκBβ, but Not IκBα, Functions as a Classical Cytoplasmic Inhibitor of NF-κB Dimers by Masking Both NF-κB Nuclear Localization Sequences in Resting CellsJournal of Biological Chemistry, 2001
- Distinct types of diffuse large B-cell lymphoma identified by gene expression profilingNature, 2000
- How NF-κB is activated: the role of the IκB kinase (IKK) complexOncogene, 1999
- The Rel/NF-κB signal transduction pathway: introductionOncogene, 1999
- Activators and target genes of Rel/NF-κB transcription factorsOncogene, 1999
- The protein truncation test: A reviewHuman Mutation, 1999
- Chromosomal localization of the genes encoding the p50/p105 subunits of NF-κB (NFKB2) and the IκB/MAD-3 (NFKBI) inhibitor of NF-κB to 4q24 and 14q13, respectivelyGenomics, 1992
- Characterization of a new human lymphoma cell line (RC-K8) with t(11;14) chromosome abnormalityCancer, 1986