Epstein-Barr Virus Immediate-Early Proteins BZLF1 and BRLF1 Activate the ATF2 Transcription Factor by Increasing the Levels of Phosphorylated p38 and c-Jun N-Terminal Kinases

Adamson, Amy L.; Darr, Dayle; Holley-Guthrie, Elizabeth; Johnson, Robert A.; Mauser, Amy; Swenson, Jennifer J.; Kenney, Shannon C.

doi:10.1128/jvi.74.3.1224-1233.2000

Cited by 164 publications

(191 citation statements)

References 86 publications

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“…Immunoblotting was performed as described previously (1). Briefly, cells were lysed in NP-40 lysis buffer supplemented with protease and phosphatase inhibitors; equivalent amounts of protein were then separated in sodium dodecyl sulfate-10% polyacrylamide gel electrophoresis gels.…”

Section: Methodsmentioning

confidence: 99%

“…Na activates c-Jun transactivator function. The ZII CRE site of Zp binds the transcription factors CREB, ATF-1, ATF-2, and c-Jun (1,34,37,63), all of which have been shown to activate Zp in reporter assays (1,34,63). Since Na activates Zp through the ZII CRE site, we examined whether Na can activate CREB, ATF-1, ATF-2, or c-Jun fusion proteins linked to the Gal4 DNA binding domain.…”

Section: Vol 78 2004 Ebv Brrf1 Protein Enhances Lytic Infection 4987mentioning

confidence: 99%

“…7A). Sequences previously shown to be important for Zp activation by a variety of different stimuli include a CRE motif (ZII) (17), which binds CREB, ATF1, ATF2, and c-Jun (1,34,37,63); a series of ZI sites (5,16,17), which bind MEF2D, Sp1, and Sp3 (22,35,36); and ZIII sites, which bind FIG. 5.…”

Section: Na Enhances R-induced Lytic Infection In a Cell-line-dependementioning

confidence: 99%

“…Z, a bZIP protein with sequence homology to c-Jun and c-Fos, binds and transactivates promoters containing AP-1-like motifs (6,13,59,61). R can also activate target promoters through direct binding (20,21,44); however, R also activates transcription indirectly through the induction of signaling cascades (1,10). Stimuli that induce a lytic infection initially activate the transcription of both IE genes (57), and the expression of either IE protein in latently infected cells is sufficient to induce the lytic form of EBV infection (7,8,45,58,64,68).…”

mentioning

confidence: 99%

“…Z transactivates the R promoter (Rp) by directly binding to Rp (2,54). In contrast, R activates Z transcription by enhancing the transcriptional functions of cellular factors (ATF-2 and c-Jun) binding to a CREB response element (CRE) motif (ZII) in the Z promoter (Zp) (1). This effect is mediated through the induction of the stressassociated mitogen-activated protein (MAP) kinases (SAPKs) p38 and c-Jun N-terminal kinase (JNK) (1), which phosphorylate and activate the transcription factors ATF-2 and c-Jun, respectively (12,23,47,62).…”

mentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

Section: Vol 78 2004 Ebv Brrf1 Protein Enhances Lytic Infection 4987mentioning

confidence: 99%

Section: Na Enhances R-induced Lytic Infection In a Cell-line-dependementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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A Specific and Covalent JNK‐1 Ligand Selected from an Encoded Self‐Assembling Chemical Library

Zimmermann

Rieder

Bajic

et al. 2017

Chemistry A European J

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We describe the construction of a DNA-encoded chemical library comprising 148'135 members, generated through the self-assembly of two sub-libraries, containing 265 and 559 members, respectively. The library was designed to contain building blocks potentially capable of forming covalent interactions with target proteins. Selections performed against JNK1, a kinase containing a conserved cysteine residue close to the ATP binding site, revealed the preferential enrichment of a 2-phenoxynicotinic acid moiety (building block A82) and a 4-(3,4-difluorophenyl)-4-oxobut-2-enoic acid moiety (building block B272). When the two compounds were joined by a short PEG linker, the resulting bidentate binder (A82-L-B272) was able to covalently modify JNK1 in the presence of a large molar excess of glutathione (0.5 mM), used to simulate intracellular reducing conditions. By contrast, derivatives of the individual building blocks were not able to covalently modify JNK1 in the same experimental conditions. The A82-L-B272 ligand was selective over related kinases (BTK and GAK), which also contain targetable cysteine residues in the vicinity of the active site. A distinction is often made between "single pharmacophore" and "dual pharmacophore" chemical libraries. In the first case, individual compounds (no matter how complex) are coupled to a DNA fragment, which serves as amplifiable identification barcode. In the second case, two building blocks are simultaneously connected to the extremities of complementary DNA strands, thus enabling the formation of combinatorial libraries by the self-assembly of oligonucleotide conjugates. [3] We have recently described a strategy for the encoding of dualpharmacophore libraries (also called "encoded self-assembling chemical libraries", or ESAC libraries), which was compatible with library decoding procedures, based on high-throughput DNA sequencing. [4] ESAC libraries may facilitate the identification of synergistic building blocks, which recognize adjacent pockets on target proteins of interest. These chemical moieties need to be subsequently connected through a suitable chemical linker, in order to display protein binding in the absence of DNA. [4,5,6] Encoded chemical libraries have previously been used for the discovery of covalent protein binders. For example, Nicolas Winssinger and coworkers previously reported the identification of reversible and irreversible covalent binders of bromodomain, [7] kinases, [8] proteases and phosphatases [9] from both DNA and PNA encoded chemical libraries. Recently, Cuozzo et al. 4 published the discovery of a potent covalent inhibitor of Bruton's tyrosine kinase (BTK), with picomolar IC 50 value from a single DNA encoded library. [10] Here, we describe the construction of a DNA-encoded self-assembling chemical library, formed by combination of 265 x 559 building blocks, yielding an ESAC library with 148'135 members. The library was designed to incorporate building blocks, which were potentially capable of forming covalent interactions with ce...

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Multiple Endocrine Neoplasia Type 1 (MEN1) 5′UTR Deletion, in MEN1 Family, Decreases Menin Expression

Kooblall

Boon

Cranston

et al. 2020

Journal of Bone and Mineral Research

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Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of parathyroid, pancreatic and pituitary tumors, and is due to mutations in the coding region of the MEN1 gene, which encodes menin. We investigated a family with identical twins that had MEN1, with different MEN1 tumors. DNA sequence analysis of the MEN1 coding region had not identified any abnormalities and we hypothesized that deletions and mutations involving the untranslated regions may be involved. Informed consent and venous blood samples were obtained from five family members. Sanger DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) analyses were performed using leukocyte DNA. This revealed a heterozygous 596bp deletion (Δ596bp) between nucleotides −1087 and −492 upstream of the translation start site, located within the MEN1 5 0 untranslated region (UTR), and includes the core promoter and multiple cis-regulatory regions. To investigate the effects of this 5 0 UTR deletion on MEN1 promoter activity, we generated luciferase reporter constructs, containing either wild-type 842bp or mutant 246bp MEN1 promoter, and transfected them into human embryonic kidney HEK293 and pancreatic neuroendocrine tumor BON-1 cells. This revealed the Δ596bp mutation to result in significant reductions by 37-fold (p < 0.0001) and 16-fold (p < 0.0001) in luciferase expression in HEK293 and BON-1 cells, respectively, compared to wild-type. The effects of this 5 0 UTR deletion on MEN1 transcription and translation were assessed using qRT-PCR and Western blot analyses, respectively, of mRNA and protein lysates obtained from Epstein-Barr-virus transformed lymphoblastoid cells derived from affected and unaffected individuals. This demonstrated the Δ596bp mutation to result in significant reductions of 84% (p < 0.05) and 88% (p < 0.05) in MEN1 mRNA and menin protein, respectively, compared to unaffected individuals. Thus, our results report the first germline MEN1 5 0 UTR mutation and highlight the importance of investigating UTRs in MEN1 patients who do not have coding region mutations.

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Epstein-Barr Virus Immediate-Early Proteins BZLF1 and BRLF1 Activate the ATF2 Transcription Factor by Increasing the Levels of Phosphorylated p38 and c-Jun N-Terminal Kinases

Cited by 164 publications

References 86 publications

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

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

A Specific and Covalent JNK‐1 Ligand Selected from an Encoded Self‐Assembling Chemical Library

Multiple Endocrine Neoplasia Type 1 (MEN1) 5′UTR Deletion, in MEN1 Family, Decreases Menin Expression

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