Modulation of cellular gene expression in B lymphoma cells following <i>in vitro</i> infection by Epstein‐Barr virus (EBV)

Calender, Alain; Cordier, M.; Billaud, Marc; Lenoir, Gilbert

doi:10.1002/ijc.2910460418

Cited by 39 publications

(22 citation statements)

References 37 publications

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“…1). Characterization of FQp, Cp and Wp promoter usage and analysis of EBV latent protein expression showed a latency III stage (data not shown) of the three EBV-converted BL cell lines, in agreement with the initial description of the cellular model (Calender et al, 1990). In agreement with the latency III stage of EBV-converted BL cells, EBV-converted cells exhibited morphologic changes such as immunoblastic and plasmablastic differentiation with expression of LMP1 and expression of the activation marker CD23 and decrease of CD77 expression (Fig.…”

Section: Phenotypic Characterization and Functional Analysis Of Ebv-csupporting

confidence: 79%

Gene Array Identification of Epstein Barr Virus-Regulated Cellular Genes in EBV-Converted Burkitt Lymphoma Cell Lines

Baran‐Marszak

Fagard

Girard

et al. 2002

Laboratory Investigation

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SUMMARY: Epstein Barr virus (EBV) is associated with various B-cell neoplasms such as post-transplant lymphoproliferativedisease or Burkitt lymphoma. B-lymphocyte reprogramming by EBV involves the control of numerous cellular genes. To identify such EBV-deregulated genes, we have compared the gene expression profile of EBV-negative Burkitt lymphoma cell lines (BL) (BL2, BL30, BL70) with their EBV-converted counterpart (BL2-B95, BL30-B95, BL70-B95) by cDNA array. Statistical analysis of the results was made using Ward's cluster analysis method. Results showed that the expression of up to 26% of the 1176 cellular genes analyzed may be modified in EBV-converted BL cells. Within this set of genes, a subset of genes markedly regulated in EBV-converted BL cells was defined as those for which expression in EBVϩ cells was increased or decreased more than 2-fold. Expression of various genes was modulated in agreement with their previously reported regulation by EBV or by transcription factors activated by EBV. Numerous genes were newly identified as modulated in EBV-converted BL cells. Some of these results were verified by both semiquantitative RT-PCR and Western blotting, and were consistent with functional studies. Functional classification of EBV-regulated genes gave a comprehensive picture of cellular reprogramming by EBV in BL , by pointing out cellular modules such as cell cycle, apoptosis, and signal transduction pathways, including BCR and TNF receptor family and interferon pathways. Furthermore, and perhaps most importantly, cDNA array results point to three families of transcription factors, Rel/NF-〉, STAT1, and Ets-related proteins Spi-B, Elf-1, and Ets-1 as putative cellular targets of

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Section: Phenotypic Characterization and Functional Analysis Of Ebv-csupporting

confidence: 79%

Gene Array Identification of Epstein Barr Virus-Regulated Cellular Genes in EBV-Converted Burkitt Lymphoma Cell Lines

Baran‐Marszak

Fagard

Girard

et al. 2002

Laboratory Investigation

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“…Various BL cell lines differ in their response to EBV latency III infection; similarities and some differences have been previously noted between BL41 and BL30 (13,14). In real-time RT-PCR assays, GS3686, ENO2, DNASE1L3, and TYK2 were at least 1.7-fold more abundant in BL30EBV than in BL30, whereas HCK, FYN, or MAP4K1 were not more abundant in BL30EBV versus BL30 (Table 2).…”

Section: Ebv-induced Genes In Lcls Versus Primary B Lymphocytesmentioning

confidence: 58%

Epstein-Barr Virus-Induced Changes in B-Lymphocyte Gene Expression

Carter

Cahir-McFarland

Kieff

2002

J Virol

134

108

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In primary Epstein-Barr virus (EBV) infection, a substantial fraction of peripheral blood B lymphocytes are latently infected and express virus-encoded proteins that are capable of causing continuous B-cell proliferation. The EBV-encoded proteins engender an unusually vigorous and large T-cell immune response which eliminates most of the virus-infected cells. In severely T-cell immune-compromised or otherwise susceptible people, the EBV-infected B lymphocytes can malignantly proliferate (reviewed in reference 90).The EBV gene products that are expressed in primary lymphocyte infection and that stimulate cell proliferation include six nuclear antigen proteins (EBNAs), two latent infection integral membrane proteins (LMPs), two small RNAs (EBERs), and BamA rightward transcripts (BARTs) of uncertain function (reviewed in reference 59). This complex infection, termed latency III, is characteristic of EBV gene expression in EBV-transformed lymphoblastoid cell lines (LCLs) and many lymphoproliferations that occur in immune-deficient humans (23, 95).Many of the EBV effects on cell growth and survival are likely to be mediated by EBV-induced changes in cell gene transcription. Five of the EBNAs can alter cell gene transcription through their direct or indirect interaction with the cellular DNA sequence-specific transcription factors RBP-j/CBF1, PU.1, and AUF1 (35,42,52,53,65,72,91,113,119,123). Furthermore, EBV LMP1 is similar to a constitutively activated CD40 receptor and activates NF-B, Jun/Fos, and AP1 cellular transcription factors (27,28,30,33,36,40,45,50,60,66,81,83). Moreover, EBV LMP2 is similar to a constitutively activated B-cell antigen receptor (BCR) in causing a stable small increase in BCR tyrosine kinase signaling and in desensitizing the cell to BCR-type signal transduction (12, 80). Four of the EBNAs that interact with cellular transcription factors and LMP1 are critical for EBV effects on cell growth and survival, while EBNA3B, LMP2, EBERs, and BARTs are not (19,37,49,56,68,73,76,92,102,108,109).In the experiments reported here, cDNA arrays were used to investigate the effects of EBV latency III infection on cell gene transcription. cDNA arrays are particularly useful in characterizing changes in expression of large numbers of cellular genes (3,4,48,51,57,74,97,100). We compared gene expression in BL41, an EBV-negative Burkitt's lymphoma (BL) cell line, with gene expression in two latency III-expressing cell lines-BL41 infected in vitro with EBV (BL41EBV) and an LCL (IB4) (18,62). In contrast to a comparison of LCLs with resting B lymphocytes, which would identify a large number of cell genes whose expression is up-regulated at various points in the cell cycle, comparison with a non-EBV-infected BL cell line will identify genes that are specifically up-regulated by EBV latency III proteins. However, EBV-regulated genes whose transcription is inherent to the BL phenotype, such as c-myc, may escape detection. MATERIALS AND METHODS Cell

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“…KR4 cells (a lymphoblastoid cell line representing type III EBV latency), BL41 EBV wild-type (WT) cells, and BL41 EBV mutant cells (P3HR1) (4,5,7) were maintained in RPMI plus 10% FBS.…”

Section: Cellsmentioning

confidence: 99%

Epstein-Barr Virus Latent Membrane Protein 1 Regulates the Function of Interferon Regulatory Factor 7 by Inducing Its Sumoylation

Bentz

Shackelford

Pagano

2012

J Virol

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Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) induces multiple signal transduction pathways during latent EBV infection via its C-terminal activating region 1 (CTAR1), CTAR2, and the less-studied CTAR3. One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications, including phosphorylation and ubiquitination. We recently documented that LMP1 induces a third major protein modification by physically interacting with the SUMO-conjugating enzyme Ubc9 through CTAR3 and inducing the sumoylation of cellular proteins in latently infected cells. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses. Our data show that endogenously sumoylated IRF7 is detected in latently infected EBV lymphoblastoid cell lines. LMP1 expression coincided with increased sumoylation of IRF7 in a CTAR3-dependent manner. Additional experiments show that LMP1 CTAR3-induced sumoylation regulates the expression and function of IRF7 by decreasing its turnover, increasing its nuclear retention, decreasing its DNA binding, and limiting its transcriptional activation. Finally, we identified that IRF7 is sumoylated at lysine 452. These data demonstrate that LMP1 CTAR3 does in fact function in intracellular signaling, leading to biologic effects. We propose that CTAR3 is an important signaling region of LMP1 that regulates protein function by sumoylation. We have shown specifically that LMP1 CTAR3, in cooperation with CTAR2, can limit the ability of IRF7 to induce innate immune responses by inducing the sumoylation of IRF7. E pstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that infects more than 90% of the world's population and establishes a lifelong infection within the host. Latent EBV infection is associated with several lymphoid tumors, including posttransplant lymphoproliferative disorder (PTLD), and AIDS-associated central nervous system (CNS) lymphomas (32, 33), which are associated with type III EBV latency. This form of latency is observed in lymphoblastoid cell lines (LCLs), which are established following EBV infection of primary B cells and exhibit sustained cellular proliferation and survival due to the constitutive activation of cellular signaling pathways. The main viral protein important in regulating these signal transduction events is latent membrane protein 1 (LMP1), an integral membrane signaling protein that mimics the tumor necrosis factor receptor family members, such as CD40, with the exception that its activation is ligand independent and it is constitutively active (22). LMP1 activates multiple signal transduction events via its C-terminal region (3, 9, 22; A. Kieser, presented at the 13th Biennial Conference of the International Association for Research on Epstein-Barr Virus and Associated Diseases, Guangzhou, China, ...

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Modulation of cellular gene expression in B lymphoma cells following in vitro infection by Epstein‐Barr virus (EBV)

Cited by 39 publications

References 37 publications

Gene Array Identification of Epstein Barr Virus-Regulated Cellular Genes in EBV-Converted Burkitt Lymphoma Cell Lines

Gene Array Identification of Epstein Barr Virus-Regulated Cellular Genes in EBV-Converted Burkitt Lymphoma Cell Lines

Epstein-Barr Virus-Induced Changes in B-Lymphocyte Gene Expression

Epstein-Barr Virus Latent Membrane Protein 1 Regulates the Function of Interferon Regulatory Factor 7 by Inducing Its Sumoylation

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