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TAF-Like Function of SV40 Large T Antigen

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TAF-Like Function of SV40 Large T Antigen Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press TAF-like function of SV40 large T antigen Blossom Damania and James C. Alwine^ Department of Microbiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6142 USA The simian virus 40 (SV40) early gene product large T antigen promiscuously activates simple promoters containing a TATA box or initiator element and at least one upstream transcription factor-binding site. Previous studies have suggested that promoter activation requires that large T antigen interacts with both the basal transcription complex and the upstream-bound factor. This mechanism of activation is similar to that proposed for TBP-associated factors (TAFs). We report genetic and biochemical evidence suggesting that large T antigen performs a TAF-like function. In the tsl3 cell line, large T antigen can rescue the temperature-sensitive (ts) defect in TAFi,250. In contrast, neither El a, small t antigen, nor mutants of large T antigen defective in transcriptional activation were able to rescue the ts defect. These data suggest that transcriptional activation by large T antigen is attributable, at least in part, to an ability to augment or replace a function of TAFn250. In addition, we show that large T antigen interacts in vitro with the Drosophila TAFs (dTAFs) dTAFiilSO, dTAFnllO, and dTAF,i40, as well as TBP. The relevance of these in vitro results was established in coimmunoprecipitation experiments using extracts of SV40-infected a3 cells that express an epitope-tagged TBP. Large T antigen was coimmunoprecipitated by antibodies to epitope-tagged TBP, endogenous TBP, hTAFiilOO, hTAFnl30, and hTAFnISO, under conditions where holo-TFIID would be precipitated. In addition, large T antigen copurified and coimmunoprecipitated with phosphocellulose-purified TFIID from SV40-infected a3 cells. Large T antigen also coprecipitated with anti-TBP antibody from extracts of tsl3 cells expressing wild-type large T antigen under conditions where the ts defect in TAF„250 was rescued. In contrast, a trans-activation mutant of large T antigen, which was unable to rescue the ts defect, failed to coprecipitate. We conclude from these data that transcriptional activation of many promoters by large T antigen results from its performing a TAF-like function in a complex with TFIID. [Key Words: TAFs; TFIID; transcription; SV40 virus; large T antigen] Received January 22, 1996; accepted in revised form April 12, 1996. The simian virus 40 (SV40) early gene product large T factor-1 (TEF-1) (Gruda et al. 1993) and Sp-1 (B. Damania antigen (T antigen) is known to be a promiscuous acti­ and J.C. Alwine, unpubl.). It is important to note that vator of many viral and cellular promoters. Such prom­ although large T antigen can interact with a component iscuity is suggested by the structural simplicity required of TFIID, it cannot activate a promoter containing only a of a promoter for activation by large T antigen; a TATA TATA element. The additional interaction with an up­ box or initiator element with at least one upstream tran­ stream-bound factor appears to be essential for activa­ scription factor-binding site (which can be variable) is tion. Such a mechanism of activation is similar to that of adequate (Gilinger and Alwine 1993; Gruda et. al 1993; the TBP-associated factors (TAFs). These components of Rice and Cole 1993). Although large T antigen is a TFIID cannot mediate transcriptional activation unless known DNA-binding protein, this function is not essen­ they interact with upstream-bound factors (Hoey et al. tial for transcriptional activation (Keller and Alwine 1993; Chen et al. 1994). These similarities in function 1985; Gallo et al. 1988, 1990; Beard and Bruggmann raise the question of whether large T antigen may per­ 1989; Zhu et al. 1991; Casaz et al. 1995). Our previous form a TAF-like function. studies have suggested that the activation of such pro­ Analysis of the Drosophila TFIID complex has shown moters requires large T antigen to interact, through pro­ that it consists of TBP and at least eight tightly bound tein-protein interactions, with both the basal transcrip­ subunits called TBP-associated factors or TAFs: tion complex and the upstream bound factors (Gilinger dTAFii250, dTAFiilSO, dTAF„I10, dTAF„80, dTAF„60, and Alwine 1993; Gruda et al. 1993). For example, we dTAFii40, dTAFii30a, and dTAFii30p (Chen et al. 1994). have shown that large T antigen can interact with The largest TAF in the TFIID complex, dTAF„250, is TATA-binding protein (TBP), transcriptional enhancer believed to provide a scaffolding function through inter­ actions with TBP and several other TAFs. The mamma­ * Corresponding author. lian TAF„250 is encoded by CCGl (Hisatake et al. 1993; GENES & DEVELOPMENT 10:1369-1381 £ 1996 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/96 $5.00 1369 Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Damania and Alwine Ruppert et al. 1993). In the temperature-sensitive (ts) Ela hamster cell line tsl3 (Talavera and Basilico \911] the ts defect results from mutation of CCGl (Sekiguchi et al. 1988; Hayashida et al. 1994; Noguchi et al. 1994). The ts defect in tsl3 cells was first characterized as a cell cycle defect because the cells arrest in Gj at the nonpermissive temperature (Talavera and Basihco 1977). How^ever, the ts defect in TAFulSO can be noted at the transcriptional level (Liu et al. 1985; Wang and Tjian 1994). At the non- permissive temperature, tsl3 cells do not exhibit a global defect in transcription, but transcription of specific genes is dramatically decreased (Wang and Tjian 1994). For example, the activity of the cyclin A (cycA) promoter is decreased by 8- to 10-fold at the nonpermissive tem­ 0.5 1 2 ^.g Effector Plasmid perature compared to its activity at the permissive tem­ perature; however, the activity of the jos promoter is relatively unaffected by the temperature (Wang and T Antigen Tjian 1994). Stable transfection of the TAFulSO gene into tsl3 cells rescues the ts defect in transcriptional activa­ tion (Wang and Tjian 1994). ^ 1.5 Previously, studies of the cell cycle phenotype of the ts defect in tsl3 cells indicated that the introduction of T antigen overcame the Gj arrest (Floros et al. 1981). This suggested to us that T antigen may be able to rescue the ts transcriptional defect in TAFulSO. In this study we 0.5 show that SV40 large T antigen can rescue the transcrip­ tional defect of TAF„250 in tsl3 cells at the nonpermis­ sive temperature. In addition, we show that large T an­ 0 12 3 tigen and TAFii250 share common in vitro interactions ^g Effector Plasmid with TAFs and TBP, and that large T antigen coimmu- Figure 1. Activation of the CycA promoter by Ela {top) and noprecipitates with TFllD from infected cell extracts. In large T antigen [bottom] in tsl3 cells at the permissive (32°C) addition, we show that large T antigen copurifies with and nonpermissive (39°C) temperatures. Two micrograms of the TFIID over phosphocellulose and coimmunoprecipitates CycA-luciferase reporter plasmid were transfected either alone with the purified TFIID. Mutants in large T antigen de­ (with filler plasmid) or with the indicated amounts of effector fective in transcriptional activation neither rescued the plasmids that expressed either Ela or large T antigen. Transfec- ts defect in TAFulSO nor coimmunoprecipitated with tions and assays were done as described in Materials and meth­ TFIID. We conclude from these findings that large T an­ ods. tigen performs a TAF-like function in a complex with TFIID. Tjian (1994). The addition of the Ela-expressing plasmid showed that Ela can activate the cycA promoter at the Results permissive temperature. Importantly, however, Ela failed to activate the promoter at the nonpermissive T antigen, like TAFjj250, can rescue the temperature. Conversely, T antigen caused very little ac­ transcriptional defect in tsl3 cells tivation at the permissive temperature; in numerous ex­ In previous studies the ts transcriptional defect in tsI3 periments the greatest activation mediated by large T cells was studied using the cycA promoter (Wang and antigen was <2.5-fold at 32°C. However, the more sig­ Tjian 1994). Hence we used the same cycA-luciferase nificant observation is that large T antigen activated the reporter plasmid in these studies. In the following trans­ cycA promoter at the nonpermissive temperature, in­ fection studies we asked whether T antigen, like wild- creasing its activity to a level approximately equal to type TAFii250, could rescue the ts defect of TAFulSO in that at the permissive temperature. These data suggest tsl3 cells. that T antigen and Ela are activating by very different Figure 1 shows the results of transfection of tsl3 cells mechanisms (see Discussion) and that T antigen, and not with the cycA reporter plasmid either alone or with in­ Ela, can rescue the ts defect in TAFii250. creasing amounts of a plasmid expressing T antigen (bot­ Figure 2 shows the results of experiments with tsl3 tom) or Ela (top). In both experiments it can be seen that cells at the nonpermissive temperature where the cycA- at the nonpermissive temperature (39°C) the cycA pro­ luciferase reporter plasmid was transfected with increas­ moter alone (the 0 effector plasmid point) showed -10% ing amounts of plasmids that express various activators of the activity seen at the permissive temperature (32°C). such as TAF,i250, T antigen, Ela, and SV40 small t an­ This is in agreement with similar studies by Wang and tigen. The results are expressed as the percentage of the 1370 GENES & DEVELOPMENT Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press TAF-like function of T antigen 300 Figure 2.
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