Home LiteratureArticle Details
PMID: 16973580 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Cellular target genes of Epstein-Barr virus nuclear antigen 2.

Journal of virology ·Vol. 80 ·No. 19 ·2006-10-00 ·Pages 9761-71

Maier S, Staffler G, Hartmann A, Höck J, Henning K, Grabusic K, Mailhammer R, Hoffmann R, Wilmanns M, Lang R, Mages J, Kempkes B

Abstract

Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA-2) is a key determinant in the EBV-driven B-cell growth transformation process. By activating an array of viral and cellular target genes, EBNA-2 initiates a cascade of events which ultimately cause cell cycle entry and the proliferation of the infected B cell. In order to identify cellular target genes that respond to EBNA-2 in the absence of other viral factors, we have performed a comprehensive search for EBNA-2 target genes in two EBV-negative B-cell lines. This screen identified 311 EBNA-2-induced and 239 EBNA-2-repressed genes that were significantly regulated in either one or both cell lines. The activation of most of these genes had not previously been attributed to EBNA-2 function and will be relevant for the identification of EBNA-2-specific contributions to EBV-associated malignancies. The diverse spectrum of EBNA-2 target genes described in this study reflects the broad spectrum of EBNA-2 functions involved in virus-host interactions, including cell signaling molecules, adapters, genes involved in cell cycle regulation, and chemokines.

MeSH Terms
B-Lymphocytes/metabolism Cell Line DNA-Binding Proteins/genetics,metabolism Down-Regulation/genetics Epstein-Barr Virus Nuclear Antigens/genetics,metabolism Herpesvirus 4, Human/genetics,metabolism Humans Oligonucleotide Array Sequence Analysis RNA, Messenger/genetics Receptors, Notch/genetics,metabolism
Chemicals
DNA-Binding Proteins Epstein-Barr Virus Nuclear Antigens RNA, Messenger Receptors, Notch
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Maier Sabine
GSF-National Research Center for Environment and Health, Institute of Clinical Molecular Biology, Munich, Germany.
Staffler Gabriele
Hartmann Andrea
Höck Julia
Henning Karen
Grabusic Kristina
Mailhammer Reinhard
Hoffmann Reinhard
Wilmanns Matthias
Lang Roland
Mages Jörg
Kempkes Bettina
References (68)
68 references, click to expand
  1. Continuous lymphoid cell lines with characteristics of B cells (bone-marrow-derived), lacking the Epstein-Barr virus genome and derived from three human lymphomas.
    Proc Natl Acad Sci U S A. 1974 Aug;71(8):3283-6 PMID: 4369887
  2. Establishment in continuous culture of a new type of lymphocyte from a "Burkitt like" malignant lymphoma (line D.G.-75).
    Int J Cancer. 1977 Jan;19(1):27-33 PMID: 188769
  3. The use of lymphomatous and lymphoblastoid cell lines in the study of Burkitt's lymphoma.
    IARC Sci Publ. 1985;(60):309-18 PMID: 3934070
  4. Epstein-Barr virus nuclear antigen 2 specifically induces expression of the B-cell activation antigen CD23.
    Proc Natl Acad Sci U S A. 1987 May;84(10):3452-6 PMID: 3033649
  5. Signalling downstream of activated mammalian Notch.
    Nature. 1995 Sep 28;377(6547):355-8 PMID: 7566092
  6. Epstein-Barr virus nuclear antigen 2-estrogen receptor fusion proteins transactivate viral and cellular genes and interact with RBP-J kappa in a conditional fashion.
    Virology. 1995 Dec 20;214(2):675-9 PMID: 8553575
  7. Epstein-Barr virus nuclear antigen 2 is a transcriptional suppressor of the immunoglobulin mu gene: implications for the expression of the translocated c-myc gene in Burkitt's lymphoma cells.
    EMBO J. 1996 Jan 15;15(2):375-82 PMID: 8617212
  8. Epstein-Barr virus nuclear antigen 2 (EBNA2)-oestrogen receptor fusion proteins complement the EBNA2-deficient Epstein-Barr virus strain P3HR1 in transformation of primary B cells but suppress growth of human B cell lymphoma lines.
    J Gen Virol. 1996 Feb;77 ( Pt 2 ):227-37 PMID: 8627226
  9. Epstein-Barr virus nuclear antigen 2 induces FcRH5 expression through CBF1.
    Blood. 2006 Jun 1;107(11):4433-9 PMID: 16439682
  10. Regulation of the ERBB-2 promoter by RBPJkappa and NOTCH.
    J Biol Chem. 1997 May 30;272(22):14110-4 PMID: 9162037
  11. Activated Notch1 modulates gene expression in B cells similarly to Epstein-Barr viral nuclear antigen 2.
    J Virol. 2000 Feb;74(4):1727-35 PMID: 10644343
  12. Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes.
    Immunity. 2000 Jul;13(1):73-84 PMID: 10933396
  13. Comparative analysis of the human and mouse Hey1 promoter: Hey genes are new Notch target genes.
    Biochem Biophys Res Commun. 2000 Aug 28;275(2):652-60 PMID: 10964718
  14. Members of the HRT family of basic helix-loop-helix proteins act as transcriptional repressors downstream of Notch signaling.
    Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13655-60 PMID: 11095750
  15. Notch signaling: from the outside in.
    Dev Biol. 2000 Dec 15;228(2):151-65 PMID: 11112321
  16. Hes7: a bHLH-type repressor gene regulated by Notch and expressed in the presomitic mesoderm.
    Genes Cells. 2001 Feb;6(2):175-85 PMID: 11260262
  17. Direct and indirect regulation of cytokine and cell cycle proteins by EBNA-2 during Epstein-Barr virus infection.
    J Virol. 2001 Apr;75(8):3537-46 PMID: 11264343
  18. Significance analysis of microarrays applied to the ionizing radiation response.
    Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21 PMID: 11309499
  19. Notch1IC partially replaces EBNA2 function in B cells immortalized by Epstein-Barr virus.
    J Virol. 2001 Jul;75(13):5899-912 PMID: 11390591
  20. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation.
    EMBO J. 2001 Jul 2;20(13):3427-36 PMID: 11432830
  21. Induction of cyclin D1 transcription and CDK2 activity by Notch(ic): implication for cell cycle disruption in transformation by Notch(ic).
    Mol Cell Biol. 2001 Sep;21(17):5925-34 PMID: 11486031
  22. Antagonistic effects of c-myc and Epstein-Barr virus latent genes on the phenotype of human B cells.
    Int J Cancer. 2001 Sep15;93(6):810-6 PMID: 11519042
  23. The Nrarp gene encodes an ankyrin-repeat protein that is transcriptionally regulated by the notch signaling pathway.
    Dev Biol. 2001 Oct 1;238(1):110-9 PMID: 11783997
  24. Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway.
    Genes Dev. 2002 Feb 1;16(3):295-300 PMID: 11825871
  25. The myc oncogene: MarvelouslY Complex.
    Adv Cancer Res. 2002;84:81-154 PMID: 11885563
  26. Expression of transcription factor AML-2 (RUNX3, CBF(alpha)-3) is induced by Epstein-Barr virus EBNA-2 and correlates with the B-cell activation phenotype.
    J Virol. 2002 May;76(10):4919-27 PMID: 11967309
  27. Genetic analysis of immortalizing functions of Epstein-Barr virus in human B lymphocytes.
    Nature. 1989 Aug 3;340(6232):393-7 PMID: 2547164
  28. Epstein-Barr virus nuclear protein 2 is a key determinant of lymphocyte transformation.
    Proc Natl Acad Sci U S A. 1989 Dec;86(23):9558-62 PMID: 2556717
  29. Stable transfection of Epstein-Barr virus (EBV) nuclear antigen 2 in lymphoma cells containing the EBV P3HR1 genome induces expression of B-cell activation molecules CD21 and CD23.
    J Virol. 1990 Mar;64(3):1002-13 PMID: 2154588
  30. The level of c-fgr RNA is increased by EBNA-2, an Epstein-Barr virus gene required for B-cell immortalization.
    J Virol. 1990 Jun;64(6):2530-6 PMID: 2159528
  31. Epstein-Barr virus-induced genes: first lymphocyte-specific G protein-coupled peptide receptors.
    J Virol. 1993 Apr;67(4):2209-20 PMID: 8383238
  32. Expression of Epstein-Barr virus proteins in primary CNS lymphoma in AIDS patients.
    Neurology. 1993 Nov;43(11):2358-62 PMID: 8232956
  33. EBNA-2 and EBNA-LP cooperate to cause G0 to G1 transition during immortalization of resting human B lymphocytes by Epstein-Barr virus.
    EMBO J. 1994 Jul 15;13(14):3321-8 PMID: 8045261
  34. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5.
    Nature. 1994 Sep 29;371(6496):419-23 PMID: 8090221
  35. Genetic and biochemical evidence that EBNA 2 interaction with a 63-kDa cellular GTG-binding protein is essential for B lymphocyte growth transformation by EBV.
    Virology. 1994 Nov 1;204(2):634-41 PMID: 7941331
  36. B-cell proliferation and induction of early G1-regulating proteins by Epstein-Barr virus mutants conditional for EBNA2.
    EMBO J. 1995 Jan 3;14(1):88-96 PMID: 7828599
  37. Expression of the chemokine receptor BLR2/EBI1 is specifically transactivated by Epstein-Barr virus nuclear antigen 2.
    Biochem Biophys Res Commun. 1995 Oct 13;215(2):737-43 PMID: 7488016
  38. Disruption of the mouse RBP-J kappa gene results in early embryonic death.
    Development. 1995 Oct;121(10):3291-301 PMID: 7588063
  39. Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia.
    Blood. 2002 May 15;99(10):3742-7 PMID: 11986231
  40. Keeping a good pathway down: transcriptional repression of Notch pathway target genes by CSL proteins.
    EMBO Rep. 2002 Sep;3(9):840-5 PMID: 12223465
  41. Epstein-barr virus-induced changes in B-lymphocyte gene expression.
    J Virol. 2002 Oct;76(20):10427-36 PMID: 12239319
  42. NF-kappaB2 is a putative target gene of activated Notch-1 via RBP-Jkappa.
    Mol Cell Biol. 1998 Apr;18(4):2077-88 PMID: 9528780
  43. Structure, chromosomal locus, and promoter of mouse Hes2 gene, a homologue of Drosophila hairy and Enhancer of split.
    Genomics. 1998 Apr 1;49(1):69-75 PMID: 9570950
  44. The proto-oncogene c-myc is a direct target gene of Epstein-Barr virus nuclear antigen 2.
    J Virol. 1999 May;73(5):4481-4 PMID: 10196351
  45. GTP-dependent secretion from neutrophils is regulated by Cdk5.
    J Biol Chem. 2004 Dec 24;279(52):53932-6 PMID: 15492003
  46. Epstein-Barr virus nuclear antigen 2 induces interleukin-18 receptor expression in B cells.
    Blood. 2005 Feb 15;105(4):1632-9 PMID: 15498855
  47. Latent membrane protein 1 of Epstein-Barr virus coordinately regulates proliferation with control of apoptosis.
    Oncogene. 2005 Mar 3;24(10):1711-7 PMID: 15674340
  48. A somatic knockout of CBF1 in a human B-cell line reveals that induction of CD21 and CCR7 by EBNA-2 is strictly CBF1 dependent and that downregulation of immunoglobulin M is partially CBF1 independent.
    J Virol. 2005 Jul;79(14):8784-92 PMID: 15994772
  49. Epstein-Barr virus nuclear antigen 2 (EBNA2) gene deletion is consistently linked with EBNA3A, -3B, and -3C expression in Burkitt's lymphoma cells and with increased resistance to apoptosis.
    J Virol. 2005 Aug;79(16):10709-17 PMID: 16051863
  50. Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies.
    Blood. 2005 Dec 1;106(12):3898-906 PMID: 16118316
  51. RNAs induced by Epstein-Barr virus nuclear antigen 2 in lymphoblastoid cell lines.
    Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1900-5 PMID: 16446431
  52. Epstein-Barr virus-associated Burkitt lymphomagenesis selects for downregulation of the nuclear antigen EBNA2.
    Nat Med. 2002 Oct;8(10):1098-104 PMID: 12219084
  53. Alemtuzumab (Campath-1H) for treatment of lymphoid malignancies in the age of nonmyeloablative conditioning?
    Bone Marrow Transplant. 2002 Dec;30(12):797-804 PMID: 12476271
  54. HES and HERP families: multiple effectors of the Notch signaling pathway.
    J Cell Physiol. 2003 Mar;194(3):237-55 PMID: 12548545
  55. The neuronal cyclin-dependent kinase 5 activator p35Nck5a and Cdk5 activity in monocytic cells.
    Leuk Lymphoma. 2003 Feb;44(2):235-40 PMID: 12688339
  56. Epstein-Barr virus-infected B cells expanding in germinal centers of infectious mononucleosis patients do not participate in the germinal center reaction.
    Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4730-5 PMID: 12665622
  57. T cell leukemia I oncogene expression depends on the presence of Epstein-Barr virus in the virus-carrying Burkitt lymphoma lines.
    Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4813-8 PMID: 12672960
  58. EBNA2 and activated Notch induce expression of BATF.
    J Virol. 2003 May;77(10):6029-40 PMID: 12719594
  59. Notch signaling regulates left-right asymmetry determination by inducing Nodal expression.
    Genes Dev. 2003 May 15;17(10):1207-12 PMID: 12730124
  60. Notch signaling induces multilineage myeloid differentiation and up-regulates PU.1 expression.
    J Immunol. 2003 Jun 1;170(11):5538-48 PMID: 12759431
  61. Basal expression of IkappaBalpha is controlled by the mammalian transcriptional repressor RBP-J (CBF1) and its activator Notch1.
    J Biol Chem. 2003 Jul 4;278(27):24359-70 PMID: 12700242
  62. Latent membrane protein 1 of Epstein-Barr virus induces CD83 by the NF-kappaB signaling pathway.
    J Virol. 2003 Aug;77(15):8290-8 PMID: 12857898
  63. Identifying biological themes within lists of genes with EASE.
    Genome Biol. 2003;4(10):R70 PMID: 14519205
  64. B cells under influence: transformation of B cells by Epstein-Barr virus.
    Nat Rev Immunol. 2003 Oct;3(10):801-12 PMID: 14523386
  65. Notch regulation of lymphocyte development and function.
    Nat Immunol. 2004 Mar;5(3):247-53 PMID: 14985712
  66. Identification of Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2) target proteins by proteome analysis: activation of EBNA2 in conditionally immortalized B cells reflects early events after infection of primary B cells by EBV.
    J Virol. 2004 Apr;78(8):3941-52 PMID: 15047810
  67. Role of NF-kappa B in cell survival and transcription of latent membrane protein 1-expressing or Epstein-Barr virus latency III-infected cells.
    J Virol. 2004 Apr;78(8):4108-19 PMID: 15047827
  68. Viral interactions with the Notch pathway.
    Semin Cancer Biol. 2004 Oct;14(5):387-96 PMID: 15288264
Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
Published
2006-10-00
Pages
9761-71
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC1617228
Subset
IM
Databases
GEO
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]