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RelB inhibits cell proliferation and tumor growth through p53 transcriptional activation

Oncogene volume 32, pages 2661–2669 (2013)Cite this article

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Abstract

The alternative nuclear factor-kappaB (NF-κB) -activation pathway proceeds via inducible p100 processing, leading to the activation of RelB-containing dimers. This pathway is aberrantly activated in several types of tumors; however, a direct role for RelB in the control of cell proliferation is still largely unexplored. Here, we demonstrate that RelB provides cell proliferation-inhibitory signals in murine fibroblasts. In agreement with these results, RelB ectopic expression inhibits xenograft tumor growth in vivo, whereas RelB knockdown enhances it. Significantly, we show that RelB inhibits cell proliferation and tumor growth in a p53-dependent manner. Mechanistic studies indicate that RelB regulates the transcription of the p53 tumor-suppressor gene through direct recruitment to the p53 promoter, thus increasing both p53 protein levels and expression of p53 target genes such as p21. Our findings define a novel link between NF-κB and growth-inhibitory pathways involving the RelB-dependent transcriptional upregulation of p53. Furthermore, they suggest that inhibition of RelB in some tumor types that retain wild-type p53 may diminish rather than improve therapeutic responses.

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Acknowledgements

We thank F Weih, U Siebenlist, K Vousden, B Vogelstein, T Jacks, J Cleveland, M Oren, D Reisman, G Kroemer, JL Perfettini, M Körner, LA Martinez, T Tchenio, J Browning and I Verma for valuable material; G Piton for technical assistance; N Boggetto for cell sorting (ImagoSeine, Institut Monod, France, Région Ile-de-France grant no. E539); and LL Pritchard for critically reading the manuscript. This work was supported by grants to VB from Agence Nationale pour la Recherche (ANR), Association pour la Recherche sur le Cancer, Belgian InterUniversity Attraction Pole, Cancéropole Ile-de-France and Université Paris Descartes, post-doctoral funding from ANR (HA and KB), doctoral fellowships from Ministère de la Recherche et des Technologies, Ligue Nationale contre le Cancer, and Société Française du Cancer (EJ), and an award from the Bettencourt-Schueller Fundation (EJ).

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Author notes

  1. E Jacque

    Present address: 4Current address: Division of Immune Cell Biology, National Institute for Medical Research, London, UK.,

  2. H Authier

    Present address: 6Current address: IRD UMR152, Université Paul Sabatier Toulouse III, Equipe Polarization des Macrophages et Récepteurs nucléaires dans les pathologies Inflammatoires et Infectieuses, Toulouse, France.,

  3. K Billot and H Authier: These authors contributed equally to this work.

Authors and Affiliations

  1. Département d’Immunologie-Hématologie, Institut Cochin- INSERM U1016, Paris, France

    E Jacque, K Billot, H Authier, D Bordereaux & V Baud

  2. Cnrs, UMR 8104, Paris, France

    E Jacque, K Billot, H Authier, D Bordereaux & V Baud

  3. Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    E Jacque, K Billot, H Authier, D Bordereaux & V Baud

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Correspondence to V Baud.

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Jacque, E., Billot, K., Authier, H. et al. RelB inhibits cell proliferation and tumor growth through p53 transcriptional activation. Oncogene 32, 2661–2669 (2013). https://doi.org/10.1038/onc.2012.282

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