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Divergent C-terminal transactivation domains of Rel/NF-κB proteins are critical determinants of their oncogenic potential in lymphocytes

Oncogene volume 23, pages 1030–1042 (2004)Cite this article

Abstract

rel/nf-κB genes are amplified, overexpressed, or constitutively activated in many human hematopoietic tumors; however, the molecular mechanisms by which they contribute to tumorigenesis remain to be determined. Here, we explored the oncogenic potential of cellular Rel/NF-κB proteins in vitro and in vivo. We show that overexpression of wild-type mouse and human c-rel genes suffices to malignantly transform primary spleen cells in stringent soft agar assays and produce fatal tumors in vivo. In contrast relA and a constitutively active form of IKKβ did not. Importantly, a hybrid RelA protein with its C-terminal transactivation domain substituted by that of v-Rel was potently oncogenic in vitro and in vivo. The transactivation domain of v-Rel selectively conferred an oncogenic phenotype upon the Rel homology domain (RHD) of RelA, but not to the more divergent RHDs of p50/NF-κB1, p52/NF-κB2, or RelB. Collectively, our results highlight important differences in the intrinsic oncogenic activity of mammalian c-Rel and RelA proteins, and indicate that critical determinants of their differential oncogenicity reside in their divergent transactivation domains. These findings provide experimental evidence for a role of mammalian Rel/NF-κB factors in leukemia/lymphomagenesis in an in vivo animal model, and are consistent with the implication of c-rel in many human lymphomas.

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Acknowledgements

We are very grateful to HR Bose, M Ernst, T Gilmore, S Ghosh, W Greene, C Paya, A Rabson, NR Rice, C Rosen, R Sen, G Sonenshein, S Tilghman, U Siebenlist, for the gifts of antibodies and reagents, to L Edelstein for making the IKKβSS-EE mutant and to D Baltimore for sharing a manuscript prior to publication. We thank AB Rabson and E White for helpful comments on the manuscript and members of the Gélinas laboratory for fruitful discussions and suggestions during the course of this work.

This work was supported by Public Health Service Grant CA54999 from the National Cancer Institute to CG. BR was a Cure for Lymphoma Foundation Fellow (Alan and Berte Hirschfield Research Grant, NY, USA) and was partially supported by the Foundation of the UMDNJ.

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  1. Béatrice Rayet

    Present address: Laboratoire de Physiologie des Membranes Cellulaires, CNRS UMR6078, Université de Nice-Sophia Antipolis, 06230, Villefranche sur Mer, France

  2. Yongjun Fan and Béatrice Rayet: These authors contributed equally

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  1. Center for Advanced Biotechnology and Medicine, Piscataway, NJ, USA

    Yongjun Fan, Béatrice Rayet & Céline Gélinas

  2. Department of Biochemistry, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, USA

    Céline Gélinas

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Fan, Y., Rayet, B. & Gélinas, C. Divergent C-terminal transactivation domains of Rel/NF-κB proteins are critical determinants of their oncogenic potential in lymphocytes. Oncogene 23, 1030–1042 (2004). https://doi.org/10.1038/sj.onc.1207221

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