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Blood, 28 May 2009, Vol. 113, No. 22, pp. 5506-5515. Prepublished online as a Blood First Edition Paper on April 1, 2009; DOI 10.1182/blood-2008-11-190090. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2008-11-190090v1 113/22/5506    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Kohlhof, H. Articles by Strobl, L. J. PubMed PubMed Citation Articles by Kohlhof, H. Articles by Strobl, L. J. Related Collections Immunobiology Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Notch1, Notch2, and Epstein-Barr virus–encoded nuclear antigen 2 signaling differentially affects proliferation and survival of Epstein-Barr virus–infected B cells Hella Kohlhof1, Franziska Hampel1, Reinhard Hoffmann2, Helmut Burtscher3, Ulrich H. Weidle3, Michael Hölzel4, Dirk Eick1, Ursula Zimber-Strobl1,*, and Lothar J. Strobl1,* 1 Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany; 2 Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany; 3 Roche Diagnostics, Pharma Research Penzberg, Penzberg, Germany; and 4 Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands The canonical mode of transcriptional activation by both the Epstein-Barr viral protein, Epstein-Barr virus–encoded nuclear antigen 2 (EBNA2), and an activated Notch receptor (Notch-IC) requires their recruitment to RBPJ, suggesting that EBNA2 uses the Notch pathway to achieve B-cell immortalization. To gain further insight into the biologic equivalence between Notch-IC and EBNA2, we performed a genome-wide expression analysis, revealing that Notch-IC and EBNA2 exhibit profound differences in the regulation of target genes. Whereas Notch-IC is more potent in regulating genes associated with differentiation and development, EBNA2 is more potent in inducing viral and cellular genes involved in proliferation, survival, and chemotaxis. Because both EBNA2 and Notch-IC induced the expression of cell cycle–associated genes, we analyzed whether Notch1-IC or Notch2-IC can replace EBNA2 in B-cell immortalization. Although Notch-IC could drive quiescent B cells into the cell cycle, B-cell immortalization was not maintained, partially due to an increased apoptosis rate in Notch-IC–expressing cells. Expression analysis revealed that both EBNA2 and Notch-IC induced the expression of proapoptotic genes, but only in EBNA2-expressing cells were antiapoptotic genes strongly up-regulated. These findings suggest that Notch signaling in B cells and B-cell lymphomas is only compatible with proliferation if pathways leading to antiapototic signals are active. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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