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A Region of Herpes Simplex Virus VP16 Can Substitute for a Transforming Domain of Epstein-Barr Virus Nuclear Protein 2 (Herpsvis/Trnrpton/Raacvaflon) JEFFREY I

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A Region of Herpes Simplex Virus VP16 Can Substitute for a Transforming Domain of Epstein-Barr Virus Nuclear Protein 2 (Herpsvis/Trnrpton/Raacvaflon) JEFFREY I Proc. Nadl. Acad. Sci. USA Vol. 89, pp. 8030-8034, September 1992 Medical Sciences A region of herpes simplex virus VP16 can substitute for a transforming domain of Epstein-Barr virus nuclear protein 2 (herpsvis/trnrpton/raacvaflon) JEFFREY I. COHEN Laboratory of Clinical Investigation, National Institutes of Health, Bethesda, MD 20892 Communicated by Bernard Moss, May 20, 1992 ABSTRACT Epstein-Barr virus (EBV) nuclear protein 2 whether hydrophobic interactions, per se, are essential for (EBNA-2) is essential for EBV-duced B-cell transformationin the function of these other activators. vitro. EBNA-2 contains a 14-amino acid domain that directly To identify critical elements in the transcriptional activa- activates transcription and Is required for transformation. To tion domain of EBNA-2 and to explore their relationship to determine whether another transcriptional activator can sub- similar elements in other acidic activators, we analyzed the stitute for this function, a chimeric virus was constructed that ability of mutated domains to activate transcription and contained a portion of the transcriptional activation domain support B-cell transformation. In addition, we replaced the from the herpes simplex virus VP16 protein inserted in place of transcriptional activation domain of EBNA-2 with a portion the 14-amino acid domain ofEBNA-2. The chimeric virus was of the activation domain of VP16, with which it shares some able to transform B cells efficiently and transactivate expres- structural features, to generate a chimeric EBNA-2-VP16 sion of EBV and B-cell genes. Randomization of the 14-amino gene. The chimeric gene was inserted into the EBV genome, acid sequence in the domain markedly reduced its transcrip- and the recombinant virus was assayed for transforming tional activating activity and the transforming efficiency of the activity in primary B cells. Finally, the chimeric protein was recombinant EBV. Mutation of a trptophan within the 14- analyzed for its ability to transactivate expression of an EBV amino acid domain ofEBNA-2 completely abolished transcrip- and B-cell gene. tional activation and B-cell trasormation. These experiments indicate that EBNA-2 and VP16 activate transcription by MATERIALS AND METHODS imilar mechaniss and that transcriptional activation is re- Cell Lines and DNAs. BJAB cells are derived from an quired for EBV-induced B-cell tansformation. EBV-negative B-cell lymphoma (16), and P3HR-1 clone 16 cells have a deletion in EBV that includes the EBNA-2 gene Epstein-Barr virus (EBV) transforms B lymphocytes in vitro (17). to proliferate indefinitely and is associated with Burkitt Plasmid GAL4 (13), which encodes the yeast GAL4 DNA lymphoma, Hodgkin disease, and certain other B-cell lym- binding domain, was linearized with BamHI and ligated to phoproliferative disorders (1). Six EBV nuclear proteins double-stranded synthetic oligonucleotides (corresponding (EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, and to the nucleotide sequence that encodes amino acids 449-483 EBNA-LP) and three latent membrane proteins (LMP-1, of EBNA-2) with Bgl II ends to generate plasmid GAL-E2 LMP-2A, and LMP2-B) are expressed in EBV-transformed B (449-483). Other synthetic oligonucleotides were used to cells in vitro (2). generate GAL-E2 WA454 (alanine substituted for tryptophan EBNA-2 is essential for transformation in vitro (3, 4) and at amino acid 454 of EBNA-2), GAL-E2 WF454 (phenylal- is expressed in tissues ofimmunocompromised patients with anine at 454), GAL-E2 WL454 (leucine at 454), GAL-E2 lymphoproliferative disease (5). EBNA-2 transactivates ex- WY454 (tyrosine at 454), GAL-E2 DN4 (asparagine or glu- pression of the EBV LMP-1 and LMP-2 genes (6, 7) and the tamine substituted for aspartic orglutamic acid, respectively, B-cell CD23, CD21, and c-fgr genes (8-10). Analysis of at amino acids 452, 455, 459, and 462 of EBNA-2), and deletion mutants shows that four domains of EBNA-2 are GAL-E2 R (randomized order of EBNA-2 amino acids 449- essential both for transformation and for transactivation of 462). GAL-E2 (449-462) was described previously (12); LMP-1 (11). Recent studies indicate that one of these four GAL-E2T1 and GAL-E2T2 were made by ligating GAL4 to domains, which encodes a 14-amino acid peptide, can di- aHinfl fragment from plasmid HK-EBNA-2 (3) and pDA1136 rectly activate transcription (12). (18), which contain EBV type 1 and type 2 EBNA-2, respec- The 14-amino acid transcriptional activation domain of tively. Synthetic oligonucleotides (corresponding to the nu- EBNA-2 is highly acidic; it contains six negatively charged cleotide sequence that encodes amino acids 439-451 ofVP16) amino acids. Other transcriptional activation domains have were used to construct GAL-VP and GAL-VP DN1 (aspar- been identified including the adenovirus ElA and the herpes agine substituted for aspartic acid at VP16 amino acid 443). simplex virus (HSV) VP16 proteins (13, 14). Analysis of the Plasmid EBNA-2d449-479 (11) was cut with Bgl II and critical elements of the HSV VP16 activation domain indi- ligated to several of the double-stranded synthetic oligonu- cates that negatively charged amino acids contribute to, but cleotides with Bgl II ends described above. The resulting are not sufficient for, transcriptional activation. Moreover, a plasmids were then cut with HindIII and Rsr I, and the large single critically situated hydrophobic amino acid in the do- fragment was ligated to the large HindIH-Rsr I fragment of main is essential for activation by VP16 (15). Although the cosmid T1EBNA-2 (3), which contains the EcoRI A fiagment distribution of hydrophobic amino acids is conserved among from an EBV type 1 strain, to generate cosmids C-E2, C-E2 several classes of transcriptional activators, it is unknown R, C-E2 WA454, C-E2 VP, and C-E2 VP DN1. The publication costs ofthis article were defrayed in part by page charge Abbreviations: EBV, Epstein-Barr virus; HSV, herpes simplex payment. This article must therefore be hereby marked "advertisement" virus; EBNA, EBV-encoded nuclear protein; LMP, latent mem- in accordance with 18 U.S.C. §1734 solely to indicate this fact. brane protein; CAT, chloramphenicol acetyltransferase. 8030 Downloaded by guest on September 28, 2021 Medical Sciences: Cohen Proc. Natl. Acad. Sci. USA 89 (1992) 8031 Transfections and Infections. Activator and reporter plas- 2A). The reporter plasmid contained GAL4 binding sites mids were cotransfected into B-lymphoma cells, and cell upstream of the murine mammary tumor virus promoter and lysates were prepared after 48 hr for chloramphenicol ace- the CAT gene (Fig. 2B; ref. 12). Activator and reporter tyltransferase (CAT) assays (12). Transformation assays plasmids were cotransfected into B-lymphoma cells, and the were performed as described (11). Infected cells were plated level of CAT activity in the cells after 48 hr was an indication into 56 wells, and the number of wells containing transform- ofthe ability ofthe EBNA-2 domain to activate transcription. ants was determined 8 weeks after infection. Two indepen- A plasmid with the GAL4 DNA binding domain alone served dent cosmid clones were prepared for each ofthe constructs. as a negative control, whereas a plasmid with the activation Polymerase Chain Reaction. Cellular DNA was amplified domain of EBNA-2 [amino acids 449-462 (12)] fused to the by using primers corresponding to nucleotides 49,590-49,606 GAL4 DNA binding domain was a positive control. and 50,073-50,089 of EBV (19) in a 35-cycle polymerase Previous work has shown that replacement of phenylala- chain reaction. The reaction products were gel purified and nine442 of VP16 with alanine completely inactivates tran- sequenced (20). scriptional activating activity (15). Replacement of tryp- tophan-454 of EBNA-2, which aligns with the phenylalanine of VP16, with alanine (E2 WA454), leucine (E2 WL454), or RESULTS tyrosine (E2 WY 454) reduced the transcriptional activation EBNA-2 and VP16 Transcriptional Activation Domains ofEBNA-2 by 80%o or more (Fig. 3). In contrast, replacement Share Common Structural Features. To identify features that of tryptophan-454 with phenylalanine (E2 WF454) retained EBNA-2 might have in common with other transcriptional over 50% ofthe transcriptional activity. Replacement offour activators, we aligned the amino acid sequence of the acti- of the negatively charged amino acids within the transcrip- vation domain of EBNA-2 from EBV types 1 and 2 with the tional activation domain (E2 DN4) or randomization of the transcriptional activation domain of HSV VP16, using the order of the amino acids in the domain (E2 R) reduced position of the hydrophobic amino acids as a guide (15). transcriptional activation by 80%6. Phenylalanine at position 442 of VP16, critical for transcrip- Replacement of the 14-amino acid transcriptional activa- tional activation by VP16, aligned with tryptophan at position tion domain of EBNA-2 (amino acids 449-462) with the 454 of EBNA-2 (Fig. 1 Upper). Although the amino acid corresponding region ofVP16 (amino acids 439-451) resulted sequences ofthe EBNA-2 and VP16 activation domains share in a 3- to 4-fold increase in the transcriptional activity [Fig. <50%6 amino acid identity, the organization ofthe hydropho- 3, GAL-VP vs. GAL-E2 (449-483)]. Replacement ofaspartic bic amino acids was similar and the negatively charged amino acid443 of VP16 with asparagine (VP DN1) did not affect acids were clustered near the carboxyl terminus of the transcriptional activation of GAL-VP. domain. When the activator constructs were cotransfected with a To determine whether the alignment ofEBNA-2 with VP16 reporter plasmid that lacked GAL4 DNA binding sites (12), was biologically relevant, constructs based on the carboxyl- there was no transcriptional activation (data not shown), terminal 14 amino acids of the domain (Fig. 1 Lower) were which verifies that direct interaction with the reporter plas- tested for their ability to activate transcription in B-lym- mid is required for activating activity.
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