Submitted November 17, 2008
Accepted March 12, 2009
Notch1, Notch2 and EBNA2 signaling differentially affects proliferation and survival of EBV-infected B cells
Hella Kohlhof, Franziska Hampel, Reinhard Hoffmann, Helmut Burtscher, Ulrich H. Weidle, Michael Holzel, Dirk Eick, Ursula Zimber-Strobl*, and Lothar J. Strobl
Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Munich, Germany
Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany
Roche Diagnostics GmbH, Pharma Research Penzberg, Department TR-ON, Penzberg, Germany
Netherlands Cancer Institute, Division of Molecular Carcinogenesis, Amsterdam, Netherlands
* Corresponding author; email: strobl{at}helmholtz-muenchen.de.
The canonical mode of transcriptional activation by both the Epstein-Barr viral protein 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 get further insight into the biological 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 inducing viral and cellular genes involved in proliferation, survival and chemotaxis. Since 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 pro-apoptotic genes, but only in EBNA2-expressing cells anti-apoptotic genes were strongly upregulated. These findings suggest that Notch signalling in B cells and B cell lymphomas is only compatible with proliferation if pathways leading to anti-apototic signals are active.
