Journal
ONCOGENE
Volume 32, Issue 21, Pages 2661-2669Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2012.282
Keywords
RelB; NF-kappa B; cell proliferation; p53
Funding
- Agence Nationale pour la Recherche (ANR)
- Association pour la Recherche sur le Cancer
- Belgian InterUniversity Attraction Pole
- Canceropole Ile-deFrance and Universite Paris Descartes,
- Ministere de la Recherche et des Technologies
- Ligue Nationale contre le Cancer
- Societe Francaise du Cancer
- Bettencourt-Schueller Fundation
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The alternative nuclear factor-kappaB (NF-kappa B) - 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-kappa B 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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