Transcriptional Cross Talk between NF-κB and p53

TLDR

Many cellular stimuli induce both p53 and NF‑κB, yet p53 promotes apoptosis while NF‑κB confers resistance, implying a regulatory mechanism that integrates these opposing outcomes. The study aims to demonstrate that p53 and NF‑κB mutually inhibit each other’s transcriptional activity in a level‑dependent manner. Using reporter plasmids in vivo, the authors showed that the inhibition is governed by the relative concentrations of the two transcription factors. They found that each factor suppresses the other’s transcriptional activation—NF‑κB inhibiting p53 transactivation and UV‑induced p53 downregulating NF‑κB—and that both compete for limited p300/CBP coactivators, a mechanism that influences apoptosis decisions and may contribute to tumorigenesis.

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.