Characterization of the CD48 gene demonstrates a positive element that is specific to Epstein-Barr virus-immortalized B-cell lines and contains an essential NF-kappa B site (original) (raw)

Abstract

Epstein-Barr virus (EBV) infection of mature, resting B cells drives them to become lymphoblasts expressing high levels of cell surface molecules, such as CD48, characteristically expressed on normal activated B cells. Here, we report on the identification of an enhancer element in the CD48 gene which reproducibly confers strong transcriptional activity only in EBV-positive B-lymphoblastoid cell lines. The element is not activated upon infection of established EBV-negative B-cell lines, indicating that EBV fails to drive these cells to a fully lymphoblastoid phenotype. An NF-kappa B binding site is an essential component of the element but alone is not sufficient to account for the activity or the specificity of the element. We have detected a specific nuclear protein complex that binds to the element and show that NF-kappa B1 (p50) is a part of this complex. The EBV-encoded latent membrane protein 1 is capable of transactivating the isolated CD48 NF-kappa B site but not the intact element, suggesting that the latent membrane protein 1-driven activation of NF-kappa B/Rel must interact with other regulatory pathways to control expression of cellular genes as EBV drives resting B cells into the cell cycle.

Full Text

The Full Text of this article is available as a PDF (536.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baichwal V. R., Sugden B. Transformation of Balb 3T3 cells by the BNLF-1 gene of Epstein-Barr virus. Oncogene. 1988 May;2(5):461–467. [PubMed] [Google Scholar]
  2. Bours V., Franzoso G., Brown K., Park S., Azarenko V., Tomita-Yamaguchi M., Kelly K., Siebenlist U. Lymphocyte activation and the family of NF-kappa B transcription factor complexes. Curr Top Microbiol Immunol. 1992;182:411–420. doi: 10.1007/978-3-642-77633-5_52. [DOI] [PubMed] [Google Scholar]
  3. Clark E. A., Lane P. J. Regulation of human B-cell activation and adhesion. Annu Rev Immunol. 1991;9:97–127. doi: 10.1146/annurev.iy.09.040191.000525. [DOI] [PubMed] [Google Scholar]
  4. Cordier M., Calender A., Billaud M., Zimber U., Rousselet G., Pavlish O., Banchereau J., Tursz T., Bornkamm G., Lenoir G. M. 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):1002–1013. doi: 10.1128/jvi.64.3.1002-1013.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cross S. L., Halden N. F., Lenardo M. J., Leonard W. J. Functionally distinct NF-kappa B binding sites in the immunoglobulin kappa and IL-2 receptor alpha chain genes. Science. 1989 Apr 28;244(4903):466–469. doi: 10.1126/science.2497520. [DOI] [PubMed] [Google Scholar]
  6. Dugas B., Delfraissy J. F., Calenda A., Peuchmaur M., Wallon C., Rannou M. T., Galanaud P. Activation and infection of B cells by Epstein-Barr virus. Role of calcium mobilization and of protein kinase C translocation. J Immunol. 1988 Dec 15;141(12):4344–4351. [PubMed] [Google Scholar]
  7. Duyao M. P., Kessler D. J., Spicer D. B., Bartholomew C., Cleveland J. L., Siekevitz M., Sonenshein G. E. Transactivation of the c-myc promoter by human T cell leukemia virus type 1 tax is mediated by NF kappa B. J Biol Chem. 1992 Aug 15;267(23):16288–16291. [PubMed] [Google Scholar]
  8. Faisst S., Meyer S. Compilation of vertebrate-encoded transcription factors. Nucleic Acids Res. 1992 Jan 11;20(1):3–26. doi: 10.1093/nar/20.1.3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fisher R. C., Thorley-Lawson D. A. Characterization of the Epstein-Barr virus-inducible gene encoding the human leukocyte adhesion and activation antigen BLAST-1 (CD48). Mol Cell Biol. 1991 Mar;11(3):1614–1623. doi: 10.1128/mcb.11.3.1614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  12. Grilli M., Chiu J. J., Lenardo M. J. NF-kappa B and Rel: participants in a multiform transcriptional regulatory system. Int Rev Cytol. 1993;143:1–62. doi: 10.1016/s0074-7696(08)61873-2. [DOI] [PubMed] [Google Scholar]
  13. Hammarskjöld M. L., Simurda M. C. Epstein-Barr virus latent membrane protein transactivates the human immunodeficiency virus type 1 long terminal repeat through induction of NF-kappa B activity. J Virol. 1992 Nov;66(11):6496–6501. doi: 10.1128/jvi.66.11.6496-6501.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hammerschmidt W., Sugden B. Genetic analysis of immortalizing functions of Epstein-Barr virus in human B lymphocytes. Nature. 1989 Aug 3;340(6232):393–397. doi: 10.1038/340393a0. [DOI] [PubMed] [Google Scholar]
  15. Kaye K. M., Izumi K. M., Kieff E. Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9150–9154. doi: 10.1073/pnas.90.19.9150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kintner C., Sugden B. Identification of antigenic determinants unique to the surfaces of cells transformed by Epstein-Barr virus. Nature. 1981 Dec 3;294(5840):458–460. doi: 10.1038/294458a0. [DOI] [PubMed] [Google Scholar]
  17. Lacy J., Rudnick H. Transcriptional regulation of the human IgE receptor (Fc epsilon RII/CD23) by EBV. Identification of EBV-responsive regulatory elements in intron 1. J Immunol. 1992 Mar 1;148(5):1554–1560. [PubMed] [Google Scholar]
  18. Lane P. J., Ledbetter J. A., McConnell F. M., Draves K., Deans J., Schieven G. L., Clark E. A. The role of tyrosine phosphorylation in signal transduction through surface Ig in human B cells. Inhibition of tyrosine phosphorylation prevents intracellular calcium release. J Immunol. 1991 Jan 15;146(2):715–722. [PubMed] [Google Scholar]
  19. Lenardo M. J., Fan C. M., Maniatis T., Baltimore D. The involvement of NF-kappa B in beta-interferon gene regulation reveals its role as widely inducible mediator of signal transduction. Cell. 1989 Apr 21;57(2):287–294. doi: 10.1016/0092-8674(89)90966-5. [DOI] [PubMed] [Google Scholar]
  20. Ling P. D., Hsieh J. J., Ruf I. K., Rawlins D. R., Hayward S. D. EBNA-2 upregulation of Epstein-Barr virus latency promoters and the cellular CD23 promoter utilizes a common targeting intermediate, CBF1. J Virol. 1994 Sep;68(9):5375–5383. doi: 10.1128/jvi.68.9.5375-5383.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. MacLennan I. C., Liu Y. L., Ling N. R. B cell proliferation in follicles, germinal centre formation and the site of neoplastic transformation in Burkitt's lymphoma. Curr Top Microbiol Immunol. 1988;141:138–148. doi: 10.1007/978-3-642-74006-0_19. [DOI] [PubMed] [Google Scholar]
  22. Maxam A. M., Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. doi: 10.1016/s0076-6879(80)65059-9. [DOI] [PubMed] [Google Scholar]
  23. Moorthy R. K., Thorley-Lawson D. A. All three domains of the Epstein-Barr virus-encoded latent membrane protein LMP-1 are required for transformation of rat-1 fibroblasts. J Virol. 1993 Mar;67(3):1638–1646. doi: 10.1128/jvi.67.3.1638-1646.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Moorthy R. K., Thorley-Lawson D. A. Biochemical, genetic, and functional analyses of the phosphorylation sites on the Epstein-Barr virus-encoded oncogenic latent membrane protein LMP-1. J Virol. 1993 May;67(5):2637–2645. doi: 10.1128/jvi.67.5.2637-2645.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Moorthy R., Thorley-Lawson D. A. Processing of the Epstein-Barr virus-encoded latent membrane protein p63/LMP. J Virol. 1990 Feb;64(2):829–837. doi: 10.1128/jvi.64.2.829-837.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rosenthal N. Identification of regulatory elements of cloned genes with functional assays. Methods Enzymol. 1987;152:704–720. doi: 10.1016/0076-6879(87)52075-4. [DOI] [PubMed] [Google Scholar]
  27. Sen R., Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell. 1986 Dec 26;47(6):921–928. doi: 10.1016/0092-8674(86)90807-x. [DOI] [PubMed] [Google Scholar]
  28. Thorley-Lawson D. A., Mann K. P. Early events in Epstein-Barr virus infection provide a model for B cell activation. J Exp Med. 1985 Jul 1;162(1):45–59. doi: 10.1084/jem.162.1.45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Thorley-Lawson D. A., Nadler L. M., Bhan A. K., Schooley R. T. BLAST-2 [EBVCS], an early cell surface marker of human B cell activation, is superinduced by Epstein Barr virus. J Immunol. 1985 May;134(5):3007–3012. [PubMed] [Google Scholar]
  30. Thorley-Lawson D. A., Schooley R. T., Bhan A. K., Nadler L. M. Epstein-Barr virus superinduces a new human B cell differentiation antigen (B-LAST 1) expressed on transformed lymphoblasts. Cell. 1982 Sep;30(2):415–425. doi: 10.1016/0092-8674(82)90239-2. [DOI] [PubMed] [Google Scholar]
  31. Tomkinson B., Robertson E., Kieff E. Epstein-Barr virus nuclear proteins EBNA-3A and EBNA-3C are essential for B-lymphocyte growth transformation. J Virol. 1993 Apr;67(4):2014–2025. doi: 10.1128/jvi.67.4.2014-2025.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Wang D., Liebowitz D., Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell. 1985 Dec;43(3 Pt 2):831–840. doi: 10.1016/0092-8674(85)90256-9. [DOI] [PubMed] [Google Scholar]
  33. Wang D., Liebowitz D., Wang F., Gregory C., Rickinson A., Larson R., Springer T., Kieff E. Epstein-Barr virus latent infection membrane protein alters the human B-lymphocyte phenotype: deletion of the amino terminus abolishes activity. J Virol. 1988 Nov;62(11):4173–4184. doi: 10.1128/jvi.62.11.4173-4184.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wang F., Gregory C., Sample C., Rowe M., Liebowitz D., Murray R., Rickinson A., Kieff E. Epstein-Barr virus latent membrane protein (LMP1) and nuclear proteins 2 and 3C are effectors of phenotypic changes in B lymphocytes: EBNA-2 and LMP1 cooperatively induce CD23. J Virol. 1990 May;64(5):2309–2318. doi: 10.1128/jvi.64.5.2309-2318.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wang F., Kikutani H., Tsang S. F., Kishimoto T., Kieff E. Epstein-Barr virus nuclear protein 2 transactivates a cis-acting CD23 DNA element. J Virol. 1991 Aug;65(8):4101–4106. doi: 10.1128/jvi.65.8.4101-4106.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Whelan J., Ghersa P., Hooft van Huijsduijnen R., Gray J., Chandra G., Talabot F., DeLamarter J. F. An NF kappa B-like factor is essential but not sufficient for cytokine induction of endothelial leukocyte adhesion molecule 1 (ELAM-1) gene transcription. Nucleic Acids Res. 1991 May 25;19(10):2645–2653. doi: 10.1093/nar/19.10.2645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Yokoyama S., Staunton D., Fisher R., Amiot M., Fortin J. J., Thorley-Lawson D. A. Expression of the Blast-1 activation/adhesion molecule and its identification as CD48. J Immunol. 1991 Apr 1;146(7):2192–2200. [PubMed] [Google Scholar]