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An optimal range of transcription potency is necessary for efficient cell transformation by c-Rel to ensure optimal nuclear localization and gene-specific activation

Oncogene volume 26, pages 4038–4043 (2007)Cite this article

Abstract

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 κB 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-1β 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.

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Acknowledgements

We are grateful to T Gilmore, H Bose, A Liss, R Hrdlicková, A Rabson and C Abate-Shen for reagents and protocols. This work was supported by NIH Grant CA54999 to CG.

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Author notes

  1. Y Fan

    Present address: Department of Molecular Genetics and Microbiology, SUNY-Stony Brook, Stony Brook, NY, 11794-5222, USA

Authors and Affiliations

  1. Center for Advanced Biotechnology and Medicine, Robert Wood Johnson Medical School, Piscataway, NJ, USA

    Y Fan & C Gélinas

  2. Department of Biochemistry, University of Medicine and Dentistry of New Jersey – Robert Wood Johnson Medical School, Piscataway, NJ, USA

    C Gélinas

  3. Cancer Institute of New Jersey, New Brunswick, NJ, USA

    C Gélinas

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  1. Y Fan
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Correspondence to C Gélinas.

Additional information

Note added in proof In agreement with our findings, Starczynowski et al. recently reported a naturally occurring mutation in the TAD of human c-Rel (Ser 525Pro) in two patients with B-cell lymphoma, that decreased its transcription potency and increased its transforming activity (Starczynowski et al., 2006).

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Fan, Y., Gélinas, C. An optimal range of transcription potency is necessary for efficient cell transformation by c-Rel to ensure optimal nuclear localization and gene-specific activation. Oncogene 26, 4038–4043 (2007). https://doi.org/10.1038/sj.onc.1210164

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