Activated Notch1 Can Transiently Substitute for EBNA2 in the Maintenance of Proliferation of LMP1-Expressing Immortalized B Cells

ABSTRACT Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2) and latent membrane protein 1 (LMP1) are essential for immortalization of human B cells by EBV. EBNA2 and activated Notch transactivate genes by interacting with the cellular transcription factor RBP-Jκ/CBF1. Therefore, EBNA2 can be regarded as a functional homologue of activated Notch. We have shown previously that the intracellular domain of Notch1 (Notch1-IC) is able to transactivate EBNA2-regulated viral promoters and to induce phenotypic changes in B cells similar to those caused by EBNA2. Here we investigated whether Notch1-IC can substitute for EBNA2 in the maintenance of B-cell proliferation. Using an EBV-immortalized lymphoblastoid cell line in which EBNA2 function can be regulated by estrogen, we demonstrate that murine Notch1-IC, in the absence of functional EBNA2, is unable to maintain LMP1 expression and to maintain cell proliferation. However, in a lymphoblastoid cell line expressing LMP1 independently of EBNA2, murine Notch1-IC can transiently maintain proliferation after EBNA2 inactivation. After 4 days, cell numbers do not increase further, and cells in the G2 phase of the cell cycle start to die. In contrast to EBNA2, murine Notch1-IC is unable to upregulate the expression of the c-myc gene in these cells.

[1]  B. Kempkes,et al.  Cell cycle activation by c‐myc in a Burkitt lymphoma model cell line , 2000, International journal of cancer.

[2]  M. Bevan,et al.  Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes. , 2000, Immunity.

[3]  T. Schroeder,et al.  Notch signalling via RBP‐J promotes myeloid differentiation , 2000, The EMBO journal.

[4]  A. Polack,et al.  Inducible loss of NF-kappaB activity is associated with apoptosis and Bcl-2 down-regulation in Epstein-Barr virus-transformed B lymphocytes. , 2000, Blood.

[5]  Georg W. Bornkamm,et al.  Activated Notch1 Modulates Gene Expression in B Cells Similarly to Epstein-Barr Viral Nuclear Antigen 2 , 2000, Journal of Virology.

[6]  U. Weidle,et al.  Control of cell growth by c-Myc in the absence of cell division , 1999, Current Biology.

[7]  N. Raab-Traub,et al.  Mimicry of CD40 signals by Epstein-Barr virus LMP1 in B lymphocyte responses. , 1999, Science.

[8]  J. Aster,et al.  Notch1 expression in early lymphopoiesis influences B versus T lineage determination. , 1999, Immunity.

[9]  T. Mak,et al.  Interleukin 13 Is Secreted by and Stimulates the Growth of Hodgkin and Reed-Sternberg Cells , 1999, The Journal of experimental medicine.

[10]  M. Ueffing,et al.  Latent membrane protein 1 of Epstein–Barr virus interacts with JAK3 and activates STAT proteins , 1999, The EMBO journal.

[11]  J. Sedivy,et al.  Mysterious liaisons: the relationship between c-Myc and the cell cycle , 1999, Oncogene.

[12]  B. Kempkes,et al.  The Proto-Oncogene c-myc Is a Direct Target Gene of Epstein-Barr Virus Nuclear Antigen 2 , 1999, Journal of Virology.

[13]  L. Miele,et al.  Notch‐1 inhibits apoptosis in murine erythroleukemia cells and is necessary for differentiation induced by hybrid polar compounds , 1999, Journal of cellular biochemistry.

[14]  H. Macdonald,et al.  Deficient T cell fate specification in mice with an induced inactivation of Notch1. , 1999, Immunity.

[15]  S. Artavanis-Tsakonas,et al.  Notch signaling: cell fate control and signal integration in development. , 1999, Science.

[16]  L. Strobl,et al.  Activated Mouse Notch1 Transactivates Epstein-Barr Virus Nuclear Antigen 2-Regulated Viral Promoters , 1999, Journal of Virology.

[17]  W. Pear,et al.  Cutting edge: protective effects of notch-1 on TCR-induced apoptosis. , 1999, Journal of immunology.

[18]  J. Sklar,et al.  Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics. , 1999, Blood.

[19]  M. Bevan,et al.  Correlating notch signaling with thymocyte maturation. , 1998, Immunity.

[20]  M. W. Young,et al.  Ligand-induced cleavage and regulation of nuclear entry of Notch in Drosophila melanogaster embryos. , 1998, Genes & development.

[21]  S. Minoguchi,et al.  Functional Replacement of the Intracellular Region of the Notch1 Receptor by Epstein-Barr Virus Nuclear Antigen 2 , 1998, Journal of Virology.

[22]  F. Schweisguth,et al.  Indirect evidence for Delta-dependent intracellular processing of Notch in Drosophila embryos , 1998, Current Biology.

[23]  Raphael Kopan,et al.  Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain , 1998, Nature.

[24]  G. Struhl,et al.  Nuclear Access and Action of Notch In Vivo , 1998, Cell.

[25]  L. Young,et al.  Activation of the cJun N-terminal kinase (JNK) pathway by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) , 1998, Oncogene.

[26]  W. Hammerschmidt,et al.  Epstein–Barr virus‐mediated B‐cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor , 1998, The EMBO journal.

[27]  W. Kolch,et al.  Epstein–Barr virus latent membrane protein‐1 triggers AP‐1 activity via the c‐Jun N‐terminal kinase cascade , 1997, The EMBO journal.

[28]  J. Karras,et al.  Induction of STAT protein signaling through the CD40 receptor in B lymphocytes: distinct STAT activation following surface Ig and CD40 receptor engagement. , 1997, Journal of immunology.

[29]  M. Ueffing,et al.  Latent membrane protein 1 of Epstein–Barr virus mimics a constitutively active receptor molecule , 1997, The EMBO journal.

[30]  J. Sedivy,et al.  Phenotypes of c-Myc-deficient rat fibroblasts isolated by targeted homologous recombination. , 1997, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[31]  E. Kieff,et al.  Epstein-Barr virus nuclear protein LP stimulates EBNA-2 acidic domain-mediated transcriptional activation , 1997, Journal of virology.

[32]  A. Rickinson,et al.  Epstein-Barr virus leader protein enhances EBNA-2-mediated transactivation of latent membrane protein 1 expression: a role for the W1W2 repeat domain , 1997, Journal of virology.

[33]  E. Robey.  Notch in vertebrates. , 1997, Current opinion in genetics & development.

[34]  S. Minoguchi,et al.  RBP-L, a transcription factor related to RBP-Jkappa , 1997, Molecular and cellular biology.

[35]  R. Geha,et al.  Jak3 is associated with CD40 and is critical for CD40 induction of gene expression in B cells. , 1997, Immunity.

[36]  J. Hsieh,et al.  Epstein-Barr virus immortalization: Notch2 interacts with CBF1 and blocks differentiation , 1997, Journal of virology.

[37]  J. Banchereau,et al.  Epstein‐Barr virus latent membrane protein (LMP1) is not sufficient to maintain proliferation of B cells but both it and activated CD40 can prolong their survival. , 1996, The EMBO journal.

[38]  I. Bernstein,et al.  Inhibition of granulocytic differentiation by mNotch1. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[39]  J. Hsieh,et al.  Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2 , 1996, Molecular and cellular biology.

[40]  H. Weintraub,et al.  Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[41]  J. Woodgett,et al.  Cross‐linking CD40 on B cells preferentially induces stress‐activated protein kinases rather than mitogen‐activated protein kinases. , 1996, The EMBO journal.

[42]  E. Kieff.  Epstein-Barr virus and its replication , 1996 .

[43]  M. Pawlita,et al.  Epstein–Barr Virus Nuclear Antigen 2–Estrogen Receptor Fusion Proteins Transactivate Viral and Cellular Genes and Interact with RBP-Jκ in a Conditional Fashion , 1995 .

[44]  F. Schweisguth,et al.  The neurogenic suppressor of hairless DNA-binding protein mediates the transcriptional activation of the enhancer of split complex genes triggered by Notch signaling. , 1995, Genes & development.

[45]  J. Posakony,et al.  Suppressor of hairless directly activates transcription of enhancer of split complex genes in response to Notch receptor activity. , 1995, Genes & development.

[46]  S. Sharma,et al.  Latent membrane protein-1 induces cyclin D2 expression, pRb hyperphosphorylation, and loss of TGF-beta 1-mediated growth inhibition in EBV-positive B cells. , 1995, Journal of immunology.

[47]  J. Hsieh,et al.  Masking of the CBF1/RBPJ kappa transcriptional repression domain by Epstein-Barr virus EBNA2. , 1995, Science.

[48]  C. Ware,et al.  The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family , 1995, Cell.

[49]  E. Kieff,et al.  Epstein-Barr virus nuclear protein 2 transactivation of the latent membrane protein 1 promoter is mediated by J kappa and PU.1 , 1995, Journal of virology.

[50]  M. Pawlita,et al.  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. , 1995, Virology.

[51]  L. Waltzer,et al.  RBP-J kappa repression activity is mediated by a co-repressor and antagonized by the Epstein-Barr virus transcription factor EBNA2. , 1995, Nucleic acids research.

[52]  L. Waltzer,et al.  The human J kappa recombination signal sequence binding protein (RBP‐J kappa) targets the Epstein‐Barr virus EBNA2 protein to its DNA responsive elements. , 1994, The EMBO journal.

[53]  F. Moreau-Gachelin,et al.  The Spi‐1/PU.1 and Spi‐B ets family transcription factors and the recombination signal binding protein RBP‐J kappa interact with an Epstein‐Barr virus nuclear antigen 2 responsive cis‐element. , 1994, The EMBO journal.

[54]  I. Berberich,et al.  Cross-linking CD40 on B cells rapidly activates nuclear factor-kappa B. , 1994, Journal of immunology.

[55]  L. Strobl,et al.  Crucial sequences within the Epstein-Barr virus TP1 promoter for EBNA2-mediated transactivation and interaction of EBNA2 with its responsive element , 1994, Journal of virology.

[56]  T. Honjo,et al.  Epstein‐Barr virus nuclear antigen 2 exerts its transactivating function through interaction with recombination signal binding protein RBP‐J kappa, the homologue of Drosophila Suppressor of Hairless. , 1994, The EMBO journal.

[57]  E. Kieff,et al.  The Epstein-Barr virus nuclear antigen 2 transactivator is directed to response elements by the J kappa recombination signal binding protein. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[58]  G. Peters,et al.  EBNA‐2 and EBNA‐LP cooperate to cause G0 to G1 transition during immortalization of resting human B lymphocytes by Epstein‐Barr virus. , 1994, The EMBO journal.

[59]  P. Ling,et al.  Mediation of Epstein-Barr virus EBNA2 transactivation by recombination signal-binding protein J kappa. , 1994, Science.

[60]  T. Honjo,et al.  The recombination signal sequence-binding protein RBP-2N functions as a transcriptional repressor , 1994, Molecular and cellular biology.

[61]  I. Bernstein,et al.  A human homologue of the Drosophila developmental gene, Notch, is expressed in CD34+ hematopoietic precursors. , 1994, Blood.

[62]  P. Ling,et al.  The Epstein-Barr virus immortalizing protein EBNA-2 is targeted to DNA by a cellular enhancer-binding protein. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[63]  E. Kieff,et al.  Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[64]  E. Kieff,et al.  Epstein-Barr virus nuclear proteins EBNA-3A and EBNA-3C are essential for B-lymphocyte growth transformation , 1993, Journal of virology.

[65]  E. Kremmer,et al.  The Epstein‐Barr virus nuclear antigen 2 interacts with an EBNA2 responsive cis‐element of the terminal protein 1 gene promoter. , 1993, The EMBO journal.

[66]  Carol D. Laherty,et al.  The Epstein-Barr virus LMP1 gene product induces A20 zinc finger protein expression by activating nuclear factor kappa B. , 1992, The Journal of biological chemistry.

[67]  G. Weinmaster,et al.  Notch2: a second mammalian Notch gene. , 1992, Development.

[68]  M. Hammarskjöld,et al.  Epstein-Barr virus latent membrane protein transactivates the human immunodeficiency virus type 1 long terminal repeat through induction of NF-kappa B activity , 1992, Journal of virology.

[69]  E. Lundgren,et al.  Transient expression of the Epstein-Barr virus LMP1 gene in human primary B cells induces cellular activation and DNA synthesis. , 1992, Oncogene.

[70]  E. Kieff,et al.  Induction of bcl-2 expression by epstein-barr virus latent membrane protein 1 protects infected B cells from programmed cell death , 1991, Cell.

[71]  E. Kieff,et al.  Epstein-Barr virus nuclear protein 2 is a key determinant of lymphocyte transformation. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[72]  W. Hammerschmidt,et al.  Genetic analysis of immortalizing functions of Epstein–Barr virus in human B lymphocytes , 1989, Nature.

[73]  J. Yates,et al.  A vector that replicates as a plasmid and can be efficiently selected in B-lymphoblasts transformed by Epstein-Barr virus , 1985, Molecular and cellular biology.

[74]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.