NF-kappa B 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 site-specific 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-kappa B. In this study, we showed that NF-kappa B 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-kappa B, but not the p50 subunit, could activate the p53 promoter. In HeLa cells, tumor necrosis factor alpha (TNF-alpha) induced NF-kappa B activity. The p53 promoter was also induced by TNF-alpha under the same conditions. Both p65 transactivation and TNF-alpha induction of the p53 promoter depended on an intact NF-kappa B site. Detailed mutational analysis of the p53 and NF-kappa B responsive elements allowed differentiation of these two responses. Thus, we show that NF-kappa B activates p53 and that this activation is inducible by TNF-alpha. Since NF-kappa B induction occurs as a response to stress and p53 arrests cells in G1/S, where repair may be initiated, activation of p53 by NF-kappa B could be a mechanism by which cells can recover from stress.
Wu
H
H
Department of Molecular Genetics, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Lozano
G
G
D001483:Base Sequence; D001665:Binding Sites; D002455:Cell Division / Q000235:genetics; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53