NF-κB activation of p53: A potential mechanism for suppressing cell growth in response to stress

The tumor suppressor p53 is a potent transcriptional activator that has been shown to regulate its own expression. In earlier studies, deletion analysis and sitespecific mutagenesis identified the p53-responsive element that fits the p53 consensus sequence. In addition, the p53-responsive element was predicted to be a binding site for NF-κB. In this study, we showed that NF-κB present in HeLa nuclear extracts could bind the same DNA element in a sequence-specific manner. Co-transfection experiments showed that the p65 subunit of NF-κB, but not the p50 subunit, could activate the p53 promoter. In HeLa cells, tumor necrosis factor a (TNF-α) induced NF-κB activity. The p53 promoter was also induced by TNF-α under the same conditions. Both p65 transactivation and TNF-α induction of the p53 promoter depended on an intact NF-κB site. Detailed mutational analysis of the p53 and NF-κB responsive elements allowed differentiation of these two responses. Thus, we show that NF-κB activates p53 and that this activation is inducible by TNF-α. Since NF-κB induction occurs as a response to stress and p53 arrests cells in G₁/S, where repair may be initiated, activation of p53 by NF-κB could be a mechanism by which cells can recover from stress.