An optimal range of transcription potency is necessary for efficient cell transformation by c-Rel to ensure optimal nuclear localization and gene-specific activation.
c-Rel is overexpressed in several B-cell lymphomas and c-rel gene overexpression can transform primary chicken lymphoid cells and induce tumors in animals. Although c-Rel is generally a stronger transcriptional activator than its viral derivative v-Rel, its oncogenic activity is significantly weaker. Among the mutations acquired during c-Rel's evolution into v-Rel are deletion of c-Rel's transactivation domain 2 (cTAD2) and mutations in cTAD1. Given the critical role of the Rel TADs in cell transformation, we investigated how mutations in c-Rel's cTAD1 and cTAD2 contribute to its oncogenicity and that of v-Rel. Mutations in cTAD2 noticeably increased c-Rel's transforming activity by promoting its nuclear localization and gene-specific transactivation, despite an overall decrease in kappaB site-dependent transactivation potency. Conversely, substitution of vTAD by cTAD1 increased v-Rel's transactivation and transforming efficiencies, whereas its substitution by the stronger cTAD2 compromised activation of mip-1beta but not irf-4 and was detrimental to cell transformation. These results suggest that the Rel TADs differentially contribute to gene-specific activation and that an optimal range of transcription potency is necessary for efficient transformation. These findings may have important implications for understanding how Rel TAD mutations can lead to a more oncogenic phenotype.
Fan
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Y
Center for Advanced Biotechnology and Medicine, Robert Wood Johnson Medical School, Piscataway, NJ 08854-5638, USA.
Gélinas
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C
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D002645:Chickens; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D047468:Immunoprecipitation; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D020572:Oncogene Proteins v-rel / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D020572:Oncogene Proteins v-rel; D020569:Proto-Oncogene Proteins c-rel