Inhibition of the RelA(p65) NF-κB Subunit by Egr-1

Abstract

Induction of transcription from the human immunodeficiency virus 1 long terminal repeat by the RelA (p65) NF-B subunit has been shown to be dependent upon an interaction with the zinc finger DNA-binding domain of Sp1. It was unknown, however, whether NF-B could also interact with other zinc finger-containing transcription factors. In this study we demonstrate that the early growth response transcription factor Egr-1, whose DNA-binding domain shares a high degree of homology with that of Sp1, can also interact with RelA in vitro and regulate NF-B transcriptional activity in vivo. Similar to the interaction with Sp1, the Rel homology domain of RelA interacts with the zinc finger domain of Egr-1. Surprisingly, and in contrast to Sp1, Egr-1 specifically represses RelA transcriptional activity through its zinc finger domain. Moreover, the interaction between RelA and the Egr-1 zinc fingers is mutually exclusive with DNA binding suggesting a model in which Egr-1 directly sequesters NF-B from its target promoters. Because Egr-1 is induced by many of the same stimuli that activate NF-B, this novel transcriptional regulatory mechanism has many implications for the involvement of both factors in cellular processes such as apoptosis and the response to stress and infection.

Opposing Roles for NF-κB/Rel Factors p65 and c-Rel in the Modulation of Neuron Survival Elicited by Glutamate and Interleukin-1β

“…Indeed, in conjunction with the selective activation of NF-B/ Rel complexes, other regulatory mechanisms may contribute to the specificity of the NF-B/Rel response. NF-B/Rel proteins can cooperate with a large number of heterologous transcription factors to either enhance (such as with the CCAAT/enhancer-binding protein ␤, SP1, and members of Fos/Jun family) or repress (such as with Egr1) NF-B-mediated transactivation (24,42). In addition, the NF-B function may be modulated through interaction with non-DNA binding transcriptional coactivators, such as the p300/CREB-binding protein, or through phosphorylation of NF-B subunits achieved by signaling pathways that modulate transcription activities (23,24,41).…”

Nuclear transcription factor-κB as a target for cancer drug development

“…Erg-1 dimerizes with the p65 (Rel A) subunit of NF-B via a specific zinc-finger domain and prevents NF-B from binding to its promotor regions on DNA. 260,261 The RAI (Rel A-associated inhibitor) gene also encodes a protein that associates with p65 (Rel A) and inhibits the anti-apoptotic activity of NF-B. RAI shares a homologous region with 53BP2, a protein involved in apoptosis regulation.…”

Sp1 and Sp3 Are Oxidative Stress-Inducible, Antideath Transcription Factors in Cortical Neurons

“…Sp1-ZnF can bind DNA but does not possess regions of the Sp1 molecule required for activation of transcription (Chapman and Perkins, 2000). As an additional control, we inserted the ␤-galactosidase (LacZ) gene into the HSV vector (HSV-LacZ).…”