The activity of the Epstein–Barr virus BamHI W promoter in B cells is dependent on the binding of CREB/ATF factors

Kirby, Helen; Rickinson, Alan B.; Bell, Andrew I.

doi:10.1099/0022-1317-81-4-1057

Cited by 33 publications

(29 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PKAcs␣ agonists have been reported to have an overall small positive effect on LMP1 expression in LCLs and on EBV Bam W EBNA promoter activity (4,18,35). The LMP1 and Bam W promoters are also positively affected by nearby CREB binding sites in some cell lines (18,35,59). The positive effects of PKA through these sites appear to be mediated by activation of an ATF-1/CREB-1 heterodimer (59).…”

Section: Vol 22 2002 Protein Kinase a Associates With Ha95 2141mentioning

confidence: 99%

Protein Kinase A Associates with HA95 and Affects Transcriptional Coactivation by Epstein-Barr Virus Nuclear Proteins

Han

Xue

Harada

et al. 2002

Molecular and Cellular Biology

View full text Add to dashboard Cite

HA95, a nuclear protein homologous to AKAP95, has been identified in immune precipitates of the EpsteinBarr virus (EBV) coactivating nuclear protein EBNA-LP from EBV-transformed lymphoblastoid cells (LCLs).We now find that HA95 and EBNA-LP are highly associated in LCLs and in B-lymphoma cells where EBNA-LP is expressed by gene transfer. Binding was also evident in yeast two-hybrid assays. HA95 binds to the EBNA-LP repeat domain that is the principal coactivator of transcription. EBNA-LP localizes with HA95 and causes HA95 to partially relocalize with EBNA-LP in promyelocytic leukemia nuclear bodies. Protein kinase A catalytic subunit ␣ (PKAcs␣) is significantly associated with HA95 in the presence or absence of EBNA-LP. Although EBNA-LP is not a PKA substrate, HA95 or PKAcs␣ expression in B lymphoblasts specifically down-regulates the strong coactivating effects of EBNA-LP. The inhibitory effects of PKAcs␣ are reversed by coexpression of protein kinase inhibitor. PKAcs␣ also inhibits EBNA-LP coactivation with the EBNA-2 acidic domain fused to the Gal4 DNA binding domain. Furthermore, EBNA-LP-and EBNA-2-induced expression of the EBV oncogene, LMP1, is down-regulated by PKAcs␣ or HA95 expression in EBV-infected lymphoblasts. These experiments indicate that HA95 and EBNA-LP localize PKAcs␣ at nuclear sites where it can affect transcription from specific promoters. The role of HA95 as a scaffold for transcriptional regulation is discussed.Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that latently infects B lymphocytes and causes their efficient proliferation into continuous lymphoblastoid cell lines (LCLs) (28, 51, 52). EBV-infected B lymphoblasts can cause lymphoproliferative diseases in immune-compromised people (53). EBV is also causally associated with Burkitt's lymphoma (BL), nasopharyngeal carcinoma, and Hodgkin's disease (11,16,27,29). Five EBV-encoded nuclear proteins, EBNA-1, -2, -3A, -3C, and -LP, and a latent-infection-associated membrane protein, LMP1, are critical for the conversion of resting B lymphocytes to LCLs (7,22,33,42,54,64). EBNA-LP and EBNA-2 are the first two EBV proteins expressed in latent infection of human B lymphocytes (2). EBNA-2 activates transcription of cellular genes, including CD21, CD23, and c-myc and of viral genes, including the EBNAs, LMP1, and LMP2 (1,2,8,17,32,60,(69)(70)(71). EBNA-2 has the intrinsic ability to self associate and recognizes promoters by binding to RBP-J and PU.1/Spi1, cellular transcription factors that recognize specific DNA sequences (20,25,26,31,58). Once associated with a promoter, the EBNA-2 acidic domain can recruit basal and activated transcription factors p300, CBP, and PCAF histone acetylases and a p100 transcriptional coactivator (25,(65)(66)(67)73). EBNA-LP strongly coactivates transcription mediated by EBNA-2 or by the EBNA-2 acidic domain (24, 47). In coactivating transcription with EBNA-2, EBNA-LP has a central role in the EBV effects on cell growth and survival.The experiments reported here focus on the role of a recently descri...

show abstract

Section: Vol 22 2002 Protein Kinase a Associates With Ha95 2141mentioning

confidence: 99%

Protein Kinase A Associates with HA95 and Affects Transcriptional Coactivation by Epstein-Barr Virus Nuclear Proteins

Han

Xue

Harada

et al. 2002

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…This promoter usually ceases to function within days as the cells differentiate into blasts and divide, and a second promoter, the Bam Cp, begins to support expression of these genes (8-10). It is not known how Wp is regulated in infected primary B cells, but transfection experiments in EBVnegative B cell lines indicate that CREB͞ATF factors regulate Wp positively (11). Similarly, it is not known how Cp is regulated in infected primary B cells, but transfection experiments in both EBV-negative and -positive B cell lines indicate that multiple cellular factors affect Cp and that EBNA1, cellular Sp1, and NFY may positively regulate Cp together (12)(13)(14)(15).…”

Section: ⌬Ur1-ebna1 Is Defective For Supporting Transcription From Thmentioning

confidence: 99%

Transcriptional activation by EBV nuclear antigen 1 is essential for the expression of EBV's transforming genes

Altmann

Pich

Ruiss

et al. 2006

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

127

123

View full text Add to dashboard Cite

EBV is a paradigm for human tumor viruses because, although it infects most people benignly, it also can cause a variety of cancers. Both in vivo and in vitro, EBV infects B lymphocytes in G0, induces them to become blasts, and can maintain their proliferation in cell culture or in vivo as tumors. How EBV succeeds in these contrasting cellular environments in expressing its genes that control the host has not been explained. We have genetically dissected the EBV nuclear antigen 1 (EBNA1) gene that is required for replication of the viral genome, to elucidate its possible role in the transcription of viral genes. Strikingly, EBNA1 is essential to drive transcription of EBV's transforming genes after infection of primary B lymphocytes.transcriptional regulation ͉ high-mobility group A protein ͉ HMGA1a

show abstract

“…The other is the recent identification of upstream regulatory sequences (7) which in reporter assays appear to be critical for Wp activity. These include a YY1 site within a region of the promoter responsible for its low baseline activity in a variety of cell lineages and, more importantly, binding sites for CREB family members (27), for RFX family members, and for the B-cell-specific activator protein BSAP/Pax5 (57a) within a region responsible for the promoter's high B-cell-specific activity. We noted that several of these sites contained CpG dinucleotides and were therefore potentially susceptible to the effect of methylation.…”

mentioning

confidence: 99%

Methylation of Transcription Factor Binding Sites in the Epstein-Barr Virus Latent Cycle Promoter Wp Coincides with Promoter Down-Regulation during Virus-Induced B-Cell Transformation

Tierney

Kirby

Nagra

et al. 2000

J Virol

View full text Add to dashboard Cite

Epstein-Barr virus (EBV), a human gammaherpesvirus, is largely B lymphotropic and possesses a unique set of latent cycle genes whose coordinate expression can drive the proliferation of latently infected B cells. This process can be studied in vitro, where experimental infection of resting B cells leads to the outgrowth of virus-transformed lymphoblastoid cell lines (LCLs) expressing the full range of EBV latent proteins; these include the nuclear antigens EBNA1, -2, -3A, -3B, -3C, and -LP and the latent membrane proteins LMP1, -2A, and -2B (25, 42). Immediately postinfection, viral transcription initiates from the latent cycle promoter Wp. The long primary transcripts thus produced are capable of generating all six EBNA mRNAs but appear to be preferentially, though not exclusively, processed to mRNAs encoding the EBNA2 and EBNA-LP proteins (2,13,62,63). Their appearance leads to activation of an alternative upstream promoter, Cp, from which the full complement of EBNA proteins is expressed, as well as to activation of the more distant LMP promoters (1, 54, 60, 61, 67), thereby completing the full range of latent protein expression. The activation of Cp is followed by a gradual waning of Wp transcription such that Cp is dominant over Wp in most established LCLs (4, 63).Virus-driven B-cell growth transformation is also observed in vivo during primary EBV infection. Thus, Wp, Cp, and LMP transcripts are detectable in the circulating B-cell pool of infectious mononucleosis (IM) patients (58). However, after resolution of the acute infection and establishment of a lifelong virus carrier state, virus-infected cells in the blood are only detectable within the resting memory B-cell pool (5, 32) and show a different program of viral transcription; in particular, Wp, Cp, and most if not all of the LMP promoters (with the possible exception of LMP2A) appear to be silent (41, 58). The mechanisms of promoter regulation which effect this switch to a more restricted form of virus latency are still not understood. However, some interesting potential clues have come from the study of EBV genome-positive malignancies, such as Burkitt's lymphoma (BL) and nasopharyngeal carcinoma, which also show more limited patterns of latent protein expression than do LCLs (42). In particular, Wp and Cp are silent in such tumors, and the only detectable EBNA, EBNA1, is expressed from a downstream EBNA1-specific promoter, Qp (48-50). Digestion of viral DNA from these tumors, using restriction enzymes that are either sensitive or insensitive to the presence of a methylated cytosine in the target sequence, indicated that several regions of the genome were more heavily methylated in tumor cells than in LCLs (3,4,11,20,22,31,51). These regions included the BamHI W and C fragments, within which Wp and Cp are situated, but not the region around Qp. Given the increasing evidence for methylation at CpG dinucleotides as a general mechanism of promoter silencing in eukaryotic cells (10), this raised the possibility that methylation of EBV latent promoters...

show abstract

The activity of the Epstein–Barr virus BamHI W promoter in B cells is dependent on the binding of CREB/ATF factors

Cited by 33 publications

References 46 publications

Protein Kinase A Associates with HA95 and Affects Transcriptional Coactivation by Epstein-Barr Virus Nuclear Proteins

Protein Kinase A Associates with HA95 and Affects Transcriptional Coactivation by Epstein-Barr Virus Nuclear Proteins

Transcriptional activation by EBV nuclear antigen 1 is essential for the expression of EBV's transforming genes

Methylation of Transcription Factor Binding Sites in the Epstein-Barr Virus Latent Cycle Promoter Wp Coincides with Promoter Down-Regulation during Virus-Induced B-Cell Transformation

Contact Info

Product

Resources

About