Transcriptional Cross Talk between NF-κB and p53

Abstract

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

Dual role of TMS1/ASC in death receptor signaling

“…Thus, whereas p53 may have some impact on expression of TMS1, it may be indirect. Alternatively, the regulation of TMS1 by genotoxins may involve transcriptional crosstalk between p53 and NF-kB (Webster and Perkins, 1999) as has been described for other pro-apoptotic NF-kB target genes, such as DR5 (Shetty et al, 2005).…”

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…Moreover, the tumor suppressor menin, which is mutated/deleted in parathyroid tumors, was reported to bind and suppress NF-kB activation (Heppner et al, 2001). Regarding the tumor suppressor p53, it was reported that p53 generally inhibits NF-kB function, and vice versa (Webster and Perkins, 1999); however, more complex relationships between p53 and NF-kB have emerged (see below).…”

Signals from within: the DNA-damage-induced NF-κB response

“…Two schools exist, one claiming that p53 is a prerequisite for NF-kB induction and that p53-induced NF-kB activation plays a merely apoptotic role, 64,65 the other claiming that genotoxic stress-induced p53 and NF-kB activation represent two independent parallel pathways, both activated by ATM, which might however interfere with each other's action through distinct mechanisms. 42,66,67 The first argument is based on the fact that some authors showed that the p53-null tumour cell line Saos-2 is resistant to doxorubicin or etoposideinduced NF-kB activation, while doxocycline-induced expression of p53 restores NF-kB activation. 65 The other school claims that p53-null cells such as Saos-2 or 10(1) murine embryo fibroblasts do activate NF-kB as efficiently as p53 wt cells in response to genotoxic stress.…”