EBNA2 and Activated Notch Induce Expression of BATF

Johansen, Lisa M.; Deppmann, Christopher D.; Erickson, Kimberly D.; Coffin, William F.; Thornton, Tina M.; Humphrey, Sean E.; Martin, Jennifer; Taparowsky, Elizabeth J.

doi:10.1128/jvi.77.10.6029-6040.2003

Cited by 41 publications

(48 citation statements)

References 83 publications

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“…Human oligonucleotide arrays (Affymetrix HU-133A) were used to assess changes in mRNA levels in E2HTF LCLs 24h after 4HT withdrawal (five arrays) in comparison with the same cells grown in media with 4HT (seven arrays), with newly derived WT EBNA2 LCLs (five arrays), and with an established LCL (IB4; four arrays). Of 22,000 array elements, 6,196 were detected in the nine WT LCL arrays and were analyzed for potential changes in E2HTF LCLs growing in media with 4HT versus without 4HT. When RNAs from WT LCLs and E2HTF LCLs in media with 4HT were compared with RNAs from E2HTF LCLs in media without 4HT, RNAs homologous to 78 array elements were Ͼ2-fold E2HTF-dependent; 33 were significant by Welch t test with P Ͻ 0.05 and are shown in Fig.…”

Section: E2htf Inactivation Results In Decreased C-myc and Cd23 Exprementioning

confidence: 99%

RNAs induced by Epstein–Barr virus nuclear antigen 2 in lymphoblastoid cell lines

Zhao

Maruo

Cooper

et al. 2006

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

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Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2) association with RBP-J is essential for regulation of virus and cell gene transcription and B lymphocyte transformation into infinitely proliferating lymphoblastoid cells (LCLs). To identify EBNA2-regulated cell genes in LCLs, an EBV recombinant that expresses EBNA2 with its C terminus fused in frame to a 4-hydroxytamoxifen (4HT)-dependent mutant estrogen receptor (E2HTF) was used to transform primary B lymphocytes to LCLs. In the presence of 4HT, E2HTF expression level and effects on the LMP1 promoter in transfected BJAB lymphoblasts were similar to EBNA2. In 4HT-supplemented medium, E2HTF EBV recombinant infected LCLs were also similar to EBNA2 LCLs in outgrowth but required higher serum and a restricted range of cell concentrations for consistent growth. In medium without 4HT, E2HTF localized to the cytoplasm, c-myc levels substantially decreased within 6 h, cells stopped growing, and levels of other EBNAs and LMP1 remained stable for 24 h. Over this 24-h period, 30 cell RNAs decreased 2-fold, and 51 other RNAs decreased 1.5-fold. These RNAs encode proteins important in cell adhesion or signaling, transcription, RNA processing, cell-cycle regulation, and survival. Real-time RT-PCR confirmed EBNA2-dependent expression of eight RNAs. RBP-J ͞CBF1 ͉ c-mycI n primary human infection, Epstein-Barr virus (EBV) establishes a latency III (LTIII) infection in B lymphocytes, which is characterized by expression of EBV-encoded nuclear antigens (EBNAs), integral membrane proteins (LMP1 and LMP2), small RNAs (EBERs), and Bam A rightward transcripts. LTIII-infected cell lymphoproliferation is limited by T cell immune responses to EBNAs and LMPs (1, 2). EBNA2 and EBNALP are the first EBV proteins expressed in B lymphocyte infection (1). EBNALP and EBNA2 enhance their upstream promoters, Cp or Wp, which results in transcription of not only EBNALP and EBNA2 but also EBNA3A, EBNA3B, EBNA3C, and EBNA1 (for review see ref. 1). EBNA2 and EBNALP also turn on the EBV LMP1, LMP2B, and LMP2A promoters. EBNA2 directly or indirectly up-regulates B lymphocyte CD21, CD23, c-myc, AML2, BATF, IL16, IL18r, c-fgr, cyclin D2, cdk4, TNF-␣, lymphotoxin, HES1, and G-CSF RNAs (1, 3-7).EBNA2 stably associates with the sequence-specific DNA binding protein RBP-J ͞CBF1 (1), which has at least one cognate site within 500 bp upstream of the Cp, LMP1, LMP2A, and CD23 promoters and within the first intron of the CD21 promoter. EBNALP coactivates with EBNA2 by interaction with the EBNA2 acidic transcriptional activation domain, association with HA95 and PKA, and displacement of HP1␣ from PML bodies (1,(8)(9)(10). The EBNA2 acidic transcriptional activation domain recruits basal and activation-related transcription factors, TAF40, TFIIB, TFIIH, p300͞CBP, PCAF histone acetyltransferases, and a p100 transcription coactivator to promoters (1, 11). The EBNA2 RBP-J association and acidic activating domains are essential for B lymphocyte conversion to lymphoblastoid cells (LCLs) (1). Furthermore, EBNA3A polypept...

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Section: E2htf Inactivation Results In Decreased C-myc and Cd23 Exprementioning

confidence: 99%

RNAs induced by Epstein–Barr virus nuclear antigen 2 in lymphoblastoid cell lines

Zhao

Maruo

Cooper

et al. 2006

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

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“…While alterations in cell growth and differentiation are associated with increases in BATF expression in a number of model systems [23][24][25][26][27][28][29], the experimental approach identified here is ideally suited for future studies to identify the genetic targets of BATF transcription complexes that mediate these profound effects on cell growth.…”

Section: Discussionmentioning

confidence: 99%

“…BATF functions as a heterodimer with the Jun proteins to generate complexes that display little to no transcriptional activity when bound to AP-1 target genes [18,23,24]. BATF is expressed in hematopoietic cells and tissues [23], and we hypothesize that BATF is a critical modulator of AP-1 transcriptional events during the growth and differentiation of various blood cell lineages [23][24][25][26]. p56 lck HA-BATF mice express BATF during all stages of thymic T cell development and were created to test our hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Direct manipulation of activator protein‐1 controls thymocyte proliferation in vitro

et al. 2005

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B cell activating transcription factor (BATF) belongs to the activator protein-1 (AP-1) superfamily of basic leucine zipper transcription factors and forms heterodimers with Jun that possess minimal transcriptional activity. Mice carrying a p56 lck HA-BATF transgene were created to observe the effects of constitutive expression of this wellcharacterized AP-1 inhibitor on T cell proliferation. Consistent with the role of AP-1 in promoting the proliferation of many cell types, BATF-transgenic thymocytes proliferate poorly in vitro when stimulated with anti-CD3e and anti-CD28 antibodies or with Concanavalin A. However, when BATF-transgenic thymocytes were stimulated using a standard treatment of PMA and ionomycin, proliferation is normal. The responsiveness to PMA and ionomycin can be attributed to the dramatic disappearance of the hemagglutinin antigen (HA)-tagged BATF protein which is a PKC-dependent process caused by the down-regulation of the p56 lck proximal promoter coupled with the rapid turnover of the HA-BATF protein. These studies describe conditions of T cell stimulation that negatively influence transcription of the widely used p56 lck proximal promoter expression cassette. In addition, the unique circumstances of this regulation were exploited to demonstrate that inhibition of AP-1 activity by BATF exerts a direct, and reversible, effect on T cell proliferation in vitro.

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“…[23][24][25] Not surprisingly, the target genes of EBNA2, at least partially, overlap with those of activated Notch. 17,26,27 Fc-receptor homolog (FcRH; also called immunoglobulin superfamily receptor translocation associated [IRTA]) comprises a family of 5 recently identified genes contiguously encoded on human chromosome 1q21. [28][29][30] Three mouse FcRHs have subsequently been identified, but there is considerable divergence from the human genes.…”

Section: Introductionmentioning

confidence: 99%

“…EBNA2 is tethered to responsive viral and cellular promoters through host DNA-binding proteins, including CBF1 (also called RBP-J), [4][5][6][7] PU.1, 8 and hnRNP D. 9 EBNA2 initiates the transcription of a cascade of primary and secondary target genes that ultimately govern B-cell transformation. The relatively small group of proposed direct cellular target genes of EBNA2 includes CD23, 10 CD21, [11][12][13] C-MYC, 14 CCR7, 15 AML-2, 16 BATF, 17 and HES-1. 18 Of these, only CD23, AML-2, and C-MYC were conclusively demonstrated to be direct targets of EBNA2, as these genes did not require new protein synthesis for induction.…”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr virus nuclear antigen 2 induces FcRH5 expression through CBF1

Mohan

Dement-Brown

Maier

et al. 2006

Blood

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IntroductionEpstein-Barr virus (EBV) is a ␥-herpes virus with a widespread distribution in human populations. 1 EBV infects and immortalizes B cells and persists in the vast majority of individuals as a lifelong latent infection of the resting memory B-cell pool. 2 EBV is implicated in the etiology of a diverse range of malignancies, including Burkitt lymphoma, Hodgkin disease, and lymphomas that arise in immunosuppressed individuals. In addition, EBV is implicated in the development of a number of autoimmune diseases, including systemic lupus erythematosus. 3 EBNA2, together with EBNA-leader protein (LP), is the first viral gene expressed following infection and is absolutely required for B-cell transformation by initiating and maintaining proliferation. EBNA2 is a transcription factor with a potent transactivator domain, but without intrinsic DNA binding activity. EBNA2 is tethered to responsive viral and cellular promoters through host DNA-binding proteins, including CBF1 (also called RBP-J), 4-7 PU.1, 8 and hnRNP D. 9 EBNA2 initiates the transcription of a cascade of primary and secondary target genes that ultimately govern B-cell transformation. The relatively small group of proposed direct cellular target genes of EBNA2 includes CD23, 10 CD21, 11-13 C-MYC, 14 CCR7, 15 AML-2, 16 BATF, 17 and HES-1. 18 Of these, only CD23, AML-2, and C-MYC were conclusively demonstrated to be direct targets of EBNA2, as these genes did not require new protein synthesis for induction. Using a CBF1-deficient cell line, CD21 and CCR7 have recently been shown to strictly depend on CBF1 for induction by EBNA2. 19 AML-2, c-myc, BATF, and Hes-1 are all transcription factors, indicating there are likely to be numerous indirect targets of EBNA2. Indeed, among other genes, EBNA2 induces the tumor necrosis factor-␣ (TNF-a), cyclin D2, and interleukin-18 (IL-18) receptor genes indirectly. 20,21 In contrast, EBNA2 suppresses the transcription of the immunoglobulin (Ig) gene via CBF1-independent mechanisms. 19,22 EBNA2 is considered a viral analog of the cellular protein Notch. Accordingly, EBNA2 can functionally replace activated Notch. 23 All 4 Notch proteins interact with CBF1, and similarly to EBNA2 function by masking the transcriptional repressor domain of CBF1. [23][24][25] Not surprisingly, the target genes of EBNA2, at least partially, overlap with those of activated Notch. 17,26,27 Fc-receptor homolog (FcRH; also called immunoglobulin superfamily receptor translocation associated [IRTA]) comprises a family of 5 recently identified genes contiguously encoded on human chromosome 1q21. [28][29][30] Three mouse FcRHs have subsequently been identified, but there is considerable divergence from the human genes. 31 FcRH5 has no mouse homolog. The human FcRH genes are differentially expressed by specific B-cell subpopulations. 32,33 These genes encode transmembrane proteins with 3 to 9 Ig-like extracellular domains. All FcRH contain immunoreceptor tyrosine-based inhibitory motif (ITIM) and/or immunoreceptor tyrosine-based activation mot...

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EBNA2 and Activated Notch Induce Expression of BATF

Cited by 41 publications

References 83 publications

RNAs induced by Epstein–Barr virus nuclear antigen 2 in lymphoblastoid cell lines

RNAs induced by Epstein–Barr virus nuclear antigen 2 in lymphoblastoid cell lines

Direct manipulation of activator protein‐1 controls thymocyte proliferation in vitro

Epstein-Barr virus nuclear antigen 2 induces FcRH5 expression through CBF1

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