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Published on: January 21, 2012
RelB inhibits cell proliferation and tumor growth through p53 transcriptional activation
E Jacque1, K Billot, H Authier
1Département d'Immunologie-Hématologie, Institut Cochin- INSERM U1016, Paris, France.
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.
Insights
RelB, a component of the alternative nuclear factor-kappaB (NF-κB) pathway, inhibits cell proliferation and tumor growth by upregulating the p53 tumor suppressor. This discovery links NF-κB to growth inhibition.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- The alternative nuclear factor-kappaB (NF-κB) pathway, involving p100 processing and RelB dimers, is often dysregulated in tumors.
- The specific role of RelB in controlling cell proliferation remains largely uninvestigated.
Purpose of the Study:
- To investigate the function of RelB in cell proliferation and tumor growth.
- To elucidate the molecular mechanisms underlying RelB's effects on growth control.
Main Methods:
- Murine fibroblast cell culture and ectopic RelB expression.
- Xenograft tumor growth assays in vivo.
- Analysis of p53 and p53 target gene (p21) expression.
- Chromatin immunoprecipitation to assess RelB binding to the p53 promoter.
Main Results:
- RelB expression inhibits cell proliferation in vitro.
- Ectopic RelB suppresses xenograft tumor growth, while RelB knockdown promotes it.
- RelB's inhibitory effects on proliferation and tumor growth are dependent on p53.
- RelB directly binds to the p53 promoter, increasing p53 levels and the expression of p53 target genes like p21.
Conclusions:
- RelB acts as a tumor suppressor by transcriptionally upregulating p53.
- A novel link between the NF-κB pathway and p53-mediated growth inhibition is established.
- Targeting RelB in tumors with wild-type p53 might be counterproductive for therapy.
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