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ZAS3 Represses Nfκb-Dependent Transcription by Direct Competition for DNA Binding

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ZAS3 Represses Nfκb-Dependent Transcription by Direct Competition for DNA Binding BMB reports ZAS3 represses NFκB-dependent transcription by direct competition for DNA binding Joung-Woo Hong1 & Lai-Chu Wu2,3,* 1The Graduate School of East-West Medical Science, Kyung Hee University, Yongin 446-701, Korea, Departments 2Molecular and Cellular Biochemistry, 3Internal Medicine, College of Medicine and Public Health, The Ohio State University, Columbus, OH, 43210, USA NFκB and ZAS3 are transcription factors that control important scription of target genes including anti-apoptotic genes. Thus, cellular processes including immunity, cell survival and apop- mutations in components of the NFκB signaling pathway that tosis. Although both proteins bind the κB-motif, they produce make NFκB constitutively expressed are often implicated in opposite physiological consequences; NFκB activates tran- certain types of cancers (4). scription, promotes cell growth and is often found to be con- The ZAS family of large, separated-paired-C2H2 zinc finger stitutively expressed in cancer cells, while ZAS3 generally re- proteins also regulates transcription through binding κB-motif presses transcription, inhibits cell proliferation and is down- (5, 6). Unlike NFκB that promotes tumorigenesis, the ZAS pro- regulated in some cancers. Here, we show that ZAS3 inhibits teins are most likely tumor suppressors. Down-regulation of NFκB-dependent transcription by competing with NFκB for ZAS2 (HIVEP2) is often found in breast cancer (7), and func- the κB-motif. Transient transfection studies show that N-termi- tional loss of ZAS1 and ZAS2 is associated with poor prognosis nal 645 amino acids is sufficient to repress transcription acti- for chronic lymphocytic leukemia (8). Furthermore, ZAS3 defi- vated by NFκB, and that the identical region also possesses in- ciency has resulted in tumor formation, cell immortalization trinsic repression activity to inhibit basal transcription from a and growth acceleration (9). Hence, NFκB and ZAS, the two promoter. Finally, in vitro DNA-protein interaction analysis major families of cellular κB-binding proteins, appear to have shows that ZAS3 is able to displace NFκB by competing with opposing effects on the regulation of transcription and growth. NFκB for the κB-motif. It is conceivable that ZAS3 has ther- A recent study shows that ZAS3 inhibits NFκB by directly asso- apeutic potential for controlling aberrant activation of NFκB in ciating with TNF receptor-associated factor 2 (TRAF2), thereby various diseases. [BMB reports 2010; 43(12): 807-812] blocking nuclear translocation of NFκB (10). Consistent with these results, NFκB is constitutively expressed in ZAS3 knock- out cells (11). INTRODUCTION Although NFκB and ZAS3 proteins are able to bind similar DNA binding sites, how they cooperatively regulate tran- NFκB controls key cellular processes, including immunity, cell scription of downstream target genes and thereby how they survival and apoptosis by activating transcription of target control the switch between cell survival and death remains a genes through the κB motif (GGGRNNYYCC) (1, 2). NFκB is mystery. ubiquitously expressed in the cell, and its cellular activity is In the present study, we show that the N-terminal 645 ami- subjected to tight post-translational control. In most cell types, no acids of ZAS3 compete efficiently with NFκB for κB-motif NFκB exists as an inactive form in the cytoplasm by associat- and abolish NFκB-dependent transcription. In addition, the ing with an inhibitor, IκB. Many stimuli, such as TNFα and lip- N-terminal region possesses intrinsic repression activity. Fur- opolysaccharide (LPS), activate cellular signaling pathways that thermore, ZAS3 does not prevent overexpressed NFκB from trigger the assembly of the IκB kinase (IKK) complex. IKK phos- translocating into the nucleus. Together, these results suggest phorylates IκB and marks it for ubiquitination and degradation that DNA competition by ZAS3 alone is sufficient to repress (3). NFκB then translocates into the nucleus (at which time it is transcription activated by NFκB and that ZAS3 is an endoge- referred to as activated) and induces NFκB-dependent tran- nous κB-motif competitor with intrinsic repression activity. *Corresponding author. Tel: 1-614-293-3042; Fax: 1-614-293-5631; RESULTS E-mail: [email protected] DOI 10.5483/BMBRep.2010.43.12.807 ZAS3 represses NFκB-activated transcription by binding the κB-motif Received 2 November 2010, Accepted 6 November 2010 Previously, ZAS3 was shown to bind the κB-motif and mediate transcriptional repression (11). To extend our understanding of Keywords: DNA competition, κB-motif-binding proteins, NFκB, Transcriptional repression, ZAS3 ZAS3 function, we asked if ZAS3 could repress transcription http://bmbreports.org BMB reports 807 ZAS3 inhibits NFκB by DNA competition Joung-Woo Hong and Lai-Chu Wu activated by NFκB by binding to the κB-motif. Increasing on luciferase activity. Taken together, these data indicate that amounts of expression vectors encoding ZAS protein (amino ZAS3 represses transcription that is activated by NFκB and this acid 106 to 2013) were co-transfected into HEK293 cells to- repression requires binding of ZAS3 to the κB-motif. gether with a constant amount of expression vector encoding p65 and p50, and a reporter plasmid (p3xκB-Fos-Luc, see Fig. The N-terminal region of ZAS3 is required for repression of 1A top) containing three consecutive copies of κB-motifs and a NFκB-activated transcription c-fos minimal promoter (−65 to +109, relative to tran- To determine which part(s) of the ZAS3 protein are necessary scription start site as +1) immediately upstream of the firefly for transcriptional repression, a number of systemic truncations luciferase gene. As expected, ectopic expression of p65 and were made by deleting different structural components, one at p50 increased luciferase activity ∼10-fold more than basal a time. To assay repression, p65 and p50 were used as an acti- level. Co-expression of ZAS3 repressed the activity of p65 and vator and p3xκB-Fos-Luc as the reporter. First, either the N- or p50 up to almost the basal level in a dose-dependent manner C-terminal half was deleted from full-length ZAS3, and its re- (Fig 1A). An essentially identical result was obtained even pression activity was examined (Fig. 2A). Deleting the C-termi- when luciferase expression was activated up to ∼100-fold by nal half containing the ZASC domain had little effect, if any, increased expression of p65 and p50 (data not shown). The fact that ZAS3 expression could significantly inhibit luciferase activity induced by p65 and p50 expression suggests that ZAS represses NFκB-activated transcription. To determine whether the repression activity of ZAS is exerted through binding the κB-motif, a similar co-transfection experiment was performed with a c-fos minimal promoter containing a reporter plasmid (pFos-Luc, see Fig. 1B top), but no κB-motif. In the absence of the κB-motif, neither p65/p50 nor ZAS3 had a negative effect Fig. 2. The N-terminal portion of ZAS3 is sufficient to repress Fig. 1. ZAS3 represses NFκB-activated transcription. The indicated NFκB-activated transcription. (A) The indicated truncation deriva- luciferase reporter plasmids, diagramed above each graph, were tives of ZAS3 were tested for their ability to repress transcription cotransfected with the NFκB (p65 and p50) and FLAG-tagged activated by NFκB. Like the FLAG-tagged full-length ZAS3 protein full-length ZAS3 (amino acid 106-2013) expression vectors into used in Fig. 1, all ZAS3 proteins were tagged with octa-peptide HEK293 cells. Relative luciferase activities, which are 100 X Luc FLAG. The schematic of the FLAG-ZAS3 fusion proteins and the experiment/Lucactivated (A) or 100 X Lucexperiment/Lucbasal (B), are shown. corresponding relative luciferase activities are shown in the left Lucactivated is the normalized luciferase activity in the presence of and right, respectively. The numbers beside each diagram indicate NFκB expression vectors and in the absence of ZAS3; Lucbasal is the first and last amino acid of each protein relative to the amino the normalized luciferase activity in the absence of both NFκB acid sequences of wild-type ZAS3 (Top, left panel). Ten nano- and ZAS expression vectors. (A) ZAS3 represses luciferase expre- grams of p3xκB-Luc and 10 ng of pCH110 were cotransfected ssion activated by overexpressed NFκB. Ten nanograms of p3xκB- with or without 0.1 μg of each p65 and p50 expression plasmid Fos-Luc and 10 ng of pCH110 were cotransfected with or with- and/or 0.2 μg of each ZAS3 expression vector into HEK293 cells. out 0.1 μg of each p65 and p50 expression vector and/or in- Relative luciferase activities were determined as described in Fig. creasing (0.1, 0.2 and 0.4 μg) amount of ZAS3 expression plas- 1. (B) All overexpressed ZAS3 proteins were localized in the nu- mid into HEK293 cells. (B) ZAS3 does not affect basal transcrip- clei of transfected HEK293 cells. Four micrograms of each ZAS3 tion in the absence of the κB-motif. Ten nanograms of pFos-Luc expression plasmid was transfected into HEK293 cells. Nuclear and 10 ng of pCH110 were cotransfected with or without 0.1 μg and cytoplasmic extracts were prepared and western blot analysis of p65 and p50 expression plasmid and/or 0.4 μg of ZAS3 ex- was performed with antibodies for FLAG, hsp90 and histone H1. pression plasmid into HEK293 cells. N; nuclear extract, C; cytoplasmic extract. 808 BMB reports http://bmbreports.org ZAS3 inhibits NFκB by DNA competition Joung-Woo Hong and Lai-Chu Wu on the repression activity of ZAS3 (106-1186), but deleting the DNA binding domain (DBD) and a reporter plasmid contain- N-terminal half containing the ZASN domain resulted in a sig- ing GAL4-binding sites (p4xG-SV-Luc) (13, 14) were used (Fig. nificant loss of its repression activity (1186-2153). Next, we 3A). GAL4-ZAS3 expression vectors were co-transfected into deleted the zinc fingers in the ZASN domain, the nuclear lo- HEK293 cells with a reporter plasmid containing four consec- calization signal (NLS) region or the entire ZASN domain from utive GAL4-binding sites.
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