Transcriptional Cross Talk between NF-κB and p53

Abstract

Many cellular stimuli result in the induction of both the tumor suppressor p53 and NF-κB. In contrast to activation of p53, which is associated with the induction of apoptosis, stimulation of NF-κB 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-κB 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-κB subunit suppresses stimulation of transcription by the other factor from a reporter plasmid in vivo. Moreover, endogenous, tumor necrosis factor alpha-activated NF-κB will inhibit endogenous wild-type p53 transactivation. Following exposure to UV light, however, the converse is observed, with p53 downregulating NF-κB-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-κB can contribute to tumorigenesis and disease.

ACKNOWLEDGMENTS

We thank Lisa Anderson, Neil Chapman, Louise Copeland, and Andrew Snowden for assistance with this project; Carol Midgley, Alison Sparks, Tim Crook, Bei-Yue Wu, Gary Nabel, Alan Prescott, Richard Goodman, Ted Hupp, and David Lane for providing invaluable reagents; and members of the Division of Gene Regulation and Expression at the University of Dundee, Stefan Roberts, Tom Owen-Hughes, and Julian Blow, for helpful comments, support, and critical reading of the manuscript.

N.D.P. is funded by a Royal Society University fellowship, and G.A.W. is supported by a grant from the Medical Research Council. This work was also supported in part by a grant from TENOVUS.