Epstein-Barr virus bicistronic mRNAs generated by facultative splicing code for two transcriptional trans-activators.

Manet, Évelyne; Gruffat, Henri; Trescol-Biémont, Marie-Claude; Moreno, Nicolas F.; Chambard, P.; Giot, Jean-François; Sergeant, Alain

doi:10.1002/j.1460-2075.1989.tb03576.x

Cited by 124 publications

(132 citation statements)

References 39 publications

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“…Future studies are needed to elucidate various functions of Meq by generating recombinant viruses with subtle mutations in the meq gene. The data presented here, as well as future studies with MDV Meq protein, may shed light on the role of basic leucine zipper proteins on the biology of Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus, two human herpesviruses of the Gammaherpesvirinae subfamily (36)(37)(38).…”

Section: Discussionmentioning

confidence: 87%

Marek's disease virus-encoded Meq gene is involved in transformation of lymphocytes but is dispensable for replication

Lupiani

Lee

Chen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

201

149

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Marek's disease virus (MDV) causes an acute lymphoproliferative disease in chickens, resulting in T cell lymphomas in visceral organs and peripheral nerves. Earlier studies have determined that the repeat regions of oncogenic serotype 1 MDV encode a basic leucine zipper protein, Meq, which structurally resembles the Jun͞Fos family of transcriptional activators. Meq is consistently expressed in MDV-induced tumor cells and has been suggested as the MDVassociated oncogene. To study the function of Meq, we have generated an rMd5⌬Meq virus by deleting both copies of the meq gene from the genome of a very virulent strain of MDV. Growth curves in cultured fibroblasts indicated that Meq is dispensable for in vitro virus replication. In vivo replication in lymphoid organs and feather follicular epithelium was also not impaired, suggesting that Meq is dispensable for lytic infection in chickens. Reactivation of the rMd5⌬Meq virus from peripheral blood lymphocytes was reduced, suggesting that Meq is involved but not essential for latency. Pathogenesis experiments showed that the rMd5⌬Meq virus was fully attenuated in chickens because none of the infected chickens developed Marek's disease-associated lymphomas, suggesting that Meq is involved in lymphocyte transformation. A revertant virus that restored the expression of the meq gene, showed properties similar to those of the parental virus, confirming that Meq is involved in transformation but not in lytic replication in chickens.

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Section: Discussionmentioning

confidence: 87%

Marek's disease virus-encoded Meq gene is involved in transformation of lymphocytes but is dispensable for replication

Lupiani

Lee

Chen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

201

149

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“…1A). These transcripts include two alternatively spliced bicistronic mRNAs, 4.0 and 3.0 kb in size, directed from Rp, the promoter of BRLF1, and a 1.0-kb monocistronic mRNA controlled from Zp, the promoter of BZLF1 (37). In the two cell lines the patterns of response to the two inducing chemicals were dramatically different.…”

Section: Resultsmentioning

confidence: 99%

“…Each lane of a 1% agarose-6% formaldehyde gel received cytoplasmic RNA from 2 ϫ 10 6 cells or total RNA from 3 ϫ 10 6 cells. Northern blots were probed with a 32 P-labeled 623-bp BamHI-to-PstI subfragment of BZLF1 cDNA (37,49). RNA loading was standardized by probing the blots with a 1.8-kbp portion of the ␤-actin cDNA or 370-bp NcoI/PstI fragment of the cDNA of the H1 RNA component of human RNase P (2).…”

Section: Methodsmentioning

confidence: 99%

Protein Kinase C-Independent Activation of the Epstein-Barr Virus Lytic Cycle

Gradoville¹,

Kwa²,

El-Guindy

et al. 2002

J Virol

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The protein kinase C (PKC) pathway has been considered to be essential for activation of latent EpsteinBarr virus (EBV) into the lytic cycle. The phorbol ester tetradecanoyl phorbol acetate (TPA), a PKC agonist, is one of the best understood activators of EBV lytic replication. Zp, the promoter of the EBV immediate-early gene BZLF1, whose product, ZEBRA, drives the lytic cycle, contains several phorbol ester response elements. We investigated the role of the PKC pathway in lytic cycle activation in prototype cell lines that differed dramatically in their response to inducing agents. We determined whether PKC was involved in lytic cycle induction by histone deacetylase ( The switch between latency and the productive lytic cycle of Epstein-Barr virus (EBV) has been studied extensively in cultured lymphoid cell lines, a system that is advantageous for study of the molecular mechanism of the switch. Viral genes that are expressed during latency rather than during the lytic cycle are well characterized (31). The major viral products that activate the lytic cycle, the transcriptional activators encoded by the genes BZLF1 and BRLF1, have been identified (10,11,26). A number of different stimuli have been shown to trigger the switch into the lytic cycle. These include halogenated pyrimidines (25), nutrient starvation (27), phorbol esters (61), calcium ionophores (16), transforming growth factor ␤1 (17), n-butyrate (36), specific histone deacetylase (HDAC) inhibitors such as trichostatin A (TSA) (9, 29), the demethylating agent azacytidine (5), cross-linking of surface immunoglobulin (53), superinfection with EBV stocks containing rearranged defective DNA (41, 43), and superinfection with human herpesvirus 6 (21). A general unanswered question is whether all inducing agents operate through a final common pathway.The mechanisms mediating control of EBV lytic-cycle gene expression are understood in rough outline, but many important details are missing. During latency the genes BRLF1 and BZLF1, encoding the lytic-cycle activators, are repressed. No mRNA or proteins encoded by these genes are detectable during latency (55). Inducing stimuli that activate the lytic cycle lead to expression of BRLF1 and BZLF1.

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“…In addition to the Z and R genes, the IE locus of EBV contains another open reading frame, BRRF1 (also designated Na), which lies within the first intron of the R gene and is oriented in the opposite direction (38). Na mRNA appears with early kinetics following induction of the viral lytic cycle in several latently infected B-cell lines (38,53).…”

mentioning

confidence: 99%

“…Na mRNA appears with early kinetics following induction of the viral lytic cycle in several latently infected B-cell lines (38,53). The promoter driving expression of Na (Nap) is located within the coding sequence for R, and reporter assays indicate that Nap is activated by Z (53).…”

mentioning

confidence: 99%

The BRRF1 Early Gene of Epstein-Barr Virus Encodes a Transcription Factor That Enhances Induction of Lytic Infection by BRLF1

Hong¹,

Delecluse

Gruffat

et al. 2004

J Virol

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The switch from the latent to the lytic form of Epstein-Barr virus (EBV) infection is mediated by expression of the viral immediate-early (IE) proteins, BZLF1 (Z) and BRLF1 (R). An EBV early protein, BRRF1 (Na), is encoded by the opposite strand of the BRLF1 intron, but the function of this nuclear protein in the viral life cycle is unknown. Here we demonstrate that Na enhances the R-mediated induction of lytic EBV infection in 293 cells latently infected with a recombinant EBV (R-KO) defective for the expression of both R and Na. Na also enhances R-induced lytic infections in a gastric carcinoma line (AGS) carrying the R-KO virus, although it has no effect in a Burkitt lymphoma line (BL-30) stably infected with the same mutant virus. We show that Na is a transcription factor that increases the ability of R to activate Z expression from the R-KO viral genome in 293 cells and that Na by itself activates the Z promoter (Zp) in EBV-negative cells. Na activation of Zp requires a CRE motif (ZII), and a consensus CRE motif is sufficient to transfer Na responsiveness to the heterologous E1b promoter. Furthermore, we show that Na enhances the transactivator function of a Gal4-c-Jun fusion protein but does not increase the transactivator function of other transcription factors (including ATF-1, ATF-2, and CREB) known to bind CRE motifs. Na expression in cells results in increased levels of a hyperphosphorylated form of c-Jun, suggesting a mechanism by which Na activates c-Jun. Our results indicate that Na is a transcription factor that activates the EBV Zp IE promoter through its effects on c-Jun and suggest that Na cooperates with BRLF1 to induce the lytic form of EBV infection in certain cell types.

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Epstein-Barr virus bicistronic mRNAs generated by facultative splicing code for two transcriptional trans-activators.

Cited by 124 publications

References 39 publications

Marek's disease virus-encoded Meq gene is involved in transformation of lymphocytes but is dispensable for replication

Marek's disease virus-encoded Meq gene is involved in transformation of lymphocytes but is dispensable for replication

Protein Kinase C-Independent Activation of the Epstein-Barr Virus Lytic Cycle

The BRRF1 Early Gene of Epstein-Barr Virus Encodes a Transcription Factor That Enhances Induction of Lytic Infection by BRLF1

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