ZAS3 represses NFκB-dependent transcription by direct competition for DNA binding

Abstract

NFκB and ZAS3 are transcription factors that control important cellular processes including immunity, cell survival and apoptosis. Although both proteins bind the κB-motif, they produce opposite physiological consequences; NFκB activates transcription, promotes cell growth and is often found to be constitutively expressed in cancer cells, while ZAS3 generally represses transcription, inhibits cell proliferation and is downregulated in some cancers. Here, we show that ZAS3 inhibits NFκB-dependent transcription by competing with NFκB for the κB-motif. Transient transfection studies show that N-terminal 645 amino acids is sufficient to repress transcription activated by NFκB, and that the identical region also possesses intrinsic repression activity to inhibit basal transcription from a promoter. Finally, in vitro DNA-protein interaction analysis shows that ZAS3 is able to displace NFκB by competing with NFκB for the κB-motif. It is conceivable that ZAS3 has therapeutic potential for controlling aberrant activation of NFκB in various diseases. [BMB reports 2010; 43(12): 807-812]

ZAS3 promotes TNFα-induced apoptosis by blocking NFκB-activated expression of the anti-apoptotic genes TRAF1 and TRAF2

“…These results suggest that ZAS3 enhances TNFα-induced apoptosis through repressing the transcription of TRAF1 and TRAF2 activated by NFκB. In line with this, our previous data showed that ZAS3 can compete for the κB DNA binding motif with NFκB (21). Taken together, our results strengthen the notion that ZAS3 inhibits NFκB-dependent expression of anti-apoptotic genes by directly competing for the κB-motif.…”

“…interacted with p65, p50 or the heterodimer of p65 and p50 (Fig. 3), which is consistent with the previous result that DNA-protein complexes with intermediate gel mobility between fusion proteins of ZAS3 and NFκB do not form in electrophoretic mobility shift assay (21).…”

“…Restoration of ZAS3 expression blocked the constitutive activation of NFκB in the nuclei (20). Furthermore, a gain-of-function study has also demonstrated that ZAS3 strongly represses NFκB-activated transcription by competing with NFκB for the κB-motif in vitro (21). Therefore, it has been proposed that there is a possible correlation between the tumor-inducing function and the transcription repression activity of ZAS3.…”

“…Two ZAS3 fusion proteins, GST-106-750 and GST-1497-2153, were prepared (Fig. 2B), since 645 amino acids of GST-106-750 containing the ZASN domain showed the strongest repression activity and in contrast GST-1497-2153 showed the weakest on NFκB-activated transcription (21). None of the ZAS3 fusion proteins directly http://bmbreports.org Forty-eight hours after transfection, cytoplasmic mRNA was isolated and semi-quantitative RT-PCR was performed with specific primer sets.…”

Mesodermal repression of single-minded in Drosophila embryo is mediated by a cluster of Snail-binding sites proximal to the early promoter

“…Sna is a short-range repressor with a zinc-finger motif that can mediate either quenching or direct repression of the transcription complex (15)(16)(17)(18). A 2.2-kb genomic region upstream of a sim early promoter includes five Sna-binding sites (12) (Fig.…”