Transcriptional cross talk between NF-kappaB and p53.
Many cellular stimuli result in the induction of both the tumor suppressor p53 and NF-kappaB. In contrast to activation of p53, which is associated with the induction of apoptosis, stimulation of NF-kappaB has been shown to promote resistance to programmed cell death. These observations suggest that a regulatory mechanism must exist to integrate these opposing outcomes and coordinate this critical cellular decision-making event. Here we show that both p53 and NF-kappaB inhibit each other's ability to stimulate gene expression and that this process is controlled by the relative levels of each transcription factor. Expression of either wild-type p53 or the RelA(p65) NF-kappaB subunit suppresses stimulation of transcription by the other factor from a reporter plasmid in vivo. Moreover, endogenous, tumor necrosis factor alpha-activated NF-kappaB will inhibit endogenous wild-type p53 transactivation. Following exposure to UV light, however, the converse is observed, with p53 downregulating NF-kappaB-mediated transcriptional activation. Both p53 and RelA(p65) interact with the transcriptional coactivator proteins p300 and CREB-binding protein (CBP), and we demonstrate that these results are consistent with competition for a limiting pool of p300/CBP complexes in vivo. These observations have many implications for regulation of the transcriptional decision-making mechanisms that govern cellular processes such as apoptosis. Furthermore, they suggest a previously unrealized mechanism through which dysregulated NF-kappaB can contribute to tumorigenesis and disease.
Webster
G A
GA
Department of Biochemistry, Division of Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom.
Perkins
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ND
D017209:Apoptosis / Q000235:genetics; D001667:Binding, Competitive; D002460:Cell Line; D005786:Gene Expression Regulation / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D051996:Transcription Factor RelA; D014158:Transcription, Genetic / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014466:Ultraviolet Rays
D016328:NF-kappa B; D012097:Repressor Proteins; D015534:Trans-Activators; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53