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Cell Cycle. 2013 Aug 1;12(15):2479-92. doi: 10.4161/cc.25495. Epub 2013 Jun 28.

A novel mechanism of crosstalk between the p53 and NFκB pathways: MDM2 binds and inhibits p65RelA.

Author information

1
Internal Medicine I and José Carreras Center; University of Saarland Medical Center; Homburg, Saarland, Germany.

Abstract

The inflammation regulating transcription factor NFκB and the tumor-suppressing transcription factor p53 can act as functional antagonists. Chronic inflammation (NFκB activity) may contribute to the development of cancer through the inhibition of p53 function, while, conversely, p53 activity may dampen inflammation. Here we report that the E3 ubiquitin ligase MDM2, whose gene is transcriptionally activated by both NFκB and p53, can bind and inhibit the p65RelA subunit of NFκB. The interaction is mediated through the N-terminal and the acidic/zinc finger domains of MDM2 on the one hand and through the N-terminal Rel homology domain of p65RelA on the other hand. Co-expression of MDM2 and p65RelA caused ubiquitination of the latter in the nucleus, and this modification was dependent of a functional MDM2 RING domain. Conversely, inhibition of endogenous MDM2 by small-molecule inhibitors or siRNA significantly reduced the ubiquitination of ectopic and endogenous p65RelA. MDM2 was able to equip p65RelA with mutated ubiquitin moieties capable of multiple monoubiquitination but incapable of polyubiquitination; moreover, MDM2 failed to destabilize p65RelA detectably, suggesting that the ubiquitin modification of p65RelA by MDM2 was mostly regulatory rather than stability-determining. MDM2 inhibited the NFκB-mediated transactivation of a reporter gene and the binding of NFκB to its DNA binding motif in vitro. Finally, knockdown of endogenous MDM2 increased the activity of endogenous NFκB as a transactivator. Thus, MDM2 can act as a direct negative regulator of NFκB by binding and inhibiting p65RelA.

KEYWORDS:

MDM2; inflammation; nuclear factor kappa B; p53; p65RelA; tumor suppression

PMID:
23839035
PMCID:
PMC3841326
DOI:
10.4161/cc.25495
[Indexed for MEDLINE]
Free PMC Article
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