Nuclear factor-κB (NF-κB) and p53 critically determine cancer development and progression. Defining the cross talk between these transcription factors can expand our knowledge on molecular mechanisms of tumorigenesis. Here, we show that induction of replicational stress activates NF-κB p65 and triggers its interaction with p53 in the nucleus. Experiments with knockout cells show that p65 and p53 are both required for enhanced NF-κB activity during S-phase checkpoint activation involving ataxia-telangiectasia mutated and checkpoint kinase-1. Accordingly, the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) also triggers formation of a transcriptionally active complex containing nuclear p65 and p53 on κB response elements. Gene expression analyses revealed that, independent of NF-κB activation in the cytosol, TNF-induced NF-κB-directed gene expression relies on p53. Hence, p53 is unexpectedly necessary for NF-κB-mediated gene expression induced by atypical and classical stimuli. Remarkably, data from gain- and loss-of function approaches argue that anti-apoptotic NF-κB p65 activity is constitutively evoked by a p53 hot-spot mutant frequently found in tumors. Our observations suggest explanations for the outstanding question why p53 mutations rather than p53 deletions arise in tumors of various origins.
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We thank Dr B Vogelstein for HCT-116 cells, Dr A Hoffmann for wild-type and Rel A−/− MEFs, Dr T Jacks and Dr D Tuveson for LSL-KRASG12D and LSL-p53R172H mice, Dr A Berns for TP53lox/lox mice, Dr H Nakhai for Ptf1a/p48ex1Cre/+ mice, Dr R Bernards and Dr R Agami for shRNA against p53, M Buchwald for help with electroporation, Dr A Licht for help with EMSAs, Dr Z-Q Wang and Dr W-K Min for wild-type and p53−/− MEFs and very helpful discussions and suggestions. This study was supported by DFG (SCHN 959/1-2) and SFB456 grants to GS, Landesprogramm ‘ProExzellenz’ (PE 123-2-1) to OHK, and a grant from Deutsche Krebshilfe to GS and OHK.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Oncogene website
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Schneider, G., Henrich, A., Greiner, G. et al. Cross talk between stimulated NF-κB and the tumor suppressor p53. Oncogene 29, 2795–2806 (2010). https://doi.org/10.1038/onc.2010.46
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