Inhibition of the RelA(p65) NF-kappaB subunit by Egr-1.

Induction of transcription from the human immunodeficiency virus 1 long terminal repeat by the RelA (p65) NF-kappaB 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-kappaB 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-kappaB 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-kappaB from its target promoters. Because Egr-1 is induced by many of the same stimuli that activate NF-kappaB, 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.