Notch1, Notch2, and Epstein-Barr virus-encoded nuclear antigen 2 signaling differentially affects proliferation and survival of Epstein-Barr virus-infected B cells

Blood. 2009 May 28;113(22):5506-15. doi: 10.1182/blood-2008-11-190090. Epub 2009 Apr 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / immunology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / physiology*
  • B-Lymphocytes / virology
  • Cell Proliferation* / drug effects
  • Cell Survival / drug effects
  • Cell Survival / immunology
  • Cell Transformation, Viral / immunology
  • Cells, Cultured
  • Epstein-Barr Virus Infections / immunology*
  • Epstein-Barr Virus Infections / metabolism
  • Epstein-Barr Virus Nuclear Antigens / metabolism
  • Epstein-Barr Virus Nuclear Antigens / pharmacology
  • Epstein-Barr Virus Nuclear Antigens / physiology*
  • Gene Expression Regulation / drug effects
  • Humans
  • Lymphoma, B-Cell / immunology
  • Lymphoma, B-Cell / metabolism
  • Lymphoma, B-Cell / pathology
  • Models, Biological
  • Receptor, Notch1 / metabolism
  • Receptor, Notch1 / physiology*
  • Receptor, Notch2 / metabolism
  • Receptor, Notch2 / physiology*
  • Recombinant Proteins / pharmacology
  • S Phase / drug effects
  • S Phase / immunology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Viral Proteins / metabolism
  • Viral Proteins / pharmacology
  • Viral Proteins / physiology*


  • EBNA-2 protein, Human herpesvirus 4
  • Epstein-Barr Virus Nuclear Antigens
  • NOTCH1 protein, human
  • NOTCH2 protein, human
  • Receptor, Notch1
  • Receptor, Notch2
  • Recombinant Proteins
  • Viral Proteins