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

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 2001 Feb 13

PMID 11160707

Citations 27

Authors

H Hofelmayr

L J Strobl

G Marschall

G W Bornkamm

U Zimber-Strobl

Affiliations

Soon will be listed here.

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-Jkappa/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.

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References

Lecourtois M, Schweisguth F . Indirect evidence for Delta-dependent intracellular processing of notch in Drosophila embryos. Curr Biol. 1998; 8(13):771-4. DOI: 10.1016/s0960-9822(98)70300-8. View

Kidd S, Lieber T, YOUNG M . Ligand-induced cleavage and regulation of nuclear entry of Notch in Drosophila melanogaster embryos. Genes Dev. 1998; 12(23):3728-40. PMC: 317253. DOI: 10.1101/gad.12.23.3728. View

Deftos M, He Y, Ojala E, Bevan M . Correlating notch signaling with thymocyte maturation. Immunity. 1999; 9(6):777-86. PMC: 2789684. DOI: 10.1016/s1074-7613(00)80643-3. View

Jehn B, Bielke W, Pear W, Osborne B . Cutting edge: protective effects of notch-1 on TCR-induced apoptosis. J Immunol. 1999; 162(2):635-8. View

Carlesso N, Aster J, Sklar J, Scadden D . Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics. Blood. 1999; 93(3):838-48. View

Hofelmayr H, Strobl L, Stein C, Laux G, Marschall G, Bornkamm G . Activated mouse Notch1 transactivates Epstein-Barr virus nuclear antigen 2-regulated viral promoters. J Virol. 1999; 73(4):2770-80. PMC: 104034. DOI: 10.1128/JVI.73.4.2770-2780.1999. View

Kaiser C, Laux G, Eick D, Jochner N, Bornkamm G, Kempkes B . The proto-oncogene c-myc is a direct target gene of Epstein-Barr virus nuclear antigen 2. J Virol. 1999; 73(5):4481-4. PMC: 104340. DOI: 10.1128/JVI.73.5.4481-4484.1999. View

Artavanis-Tsakonas S, Rand M, Lake R . Notch signaling: cell fate control and signal integration in development. Science. 1999; 284(5415):770-6. DOI: 10.1126/science.284.5415.770. View

Ling P, Rawlins D, Hayward S . The Epstein-Barr virus immortalizing protein EBNA-2 is targeted to DNA by a cellular enhancer-binding protein. Proc Natl Acad Sci U S A. 1993; 90(20):9237-41. PMC: 47542. DOI: 10.1073/pnas.90.20.9237. View

10.

Milner L, Kopan R, Martin D, Bernstein I . A human homologue of the Drosophila developmental gene, Notch, is expressed in CD34+ hematopoietic precursors. Blood. 1994; 83(8):2057-62. View

11.

Dou S, Zeng X, Cortes P, Erdjument-Bromage H, Tempst P, Honjo T . The recombination signal sequence-binding protein RBP-2N functions as a transcriptional repressor. Mol Cell Biol. 1994; 14(5):3310-9. PMC: 358697. DOI: 10.1128/mcb.14.5.3310-3319.1994. View

12.

Karras J, Wang Z, Huo L, Frank D, Rothstein T . Induction of STAT protein signaling through the CD40 receptor in B lymphocytes: distinct STAT activation following surface Ig and CD40 receptor engagement. J Immunol. 1997; 159(9):4350-5. View

13.

Gires O, Zimber-Strobl U, Gonnella R, Ueffing M, Marschall G, Zeidler R . Latent membrane protein 1 of Epstein-Barr virus mimics a constitutively active receptor molecule. EMBO J. 1997; 16(20):6131-40. PMC: 1326297. DOI: 10.1093/emboj/16.20.6131. View

14.

Kieser A, Kilger E, Gires O, Ueffing M, Kolch W, Hammerschmidt W . Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade. EMBO J. 1997; 16(21):6478-85. PMC: 1170253. DOI: 10.1093/emboj/16.21.6478. View

15.

Kilger E, Kieser A, Baumann M, Hammerschmidt W . Epstein-Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor. EMBO J. 1998; 17(6):1700-9. PMC: 1170517. DOI: 10.1093/emboj/17.6.1700. View

16.

Eliopoulos A, Young L . Activation of the cJun N-terminal kinase (JNK) pathway by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1). Oncogene. 1998; 16(13):1731-42. DOI: 10.1038/sj.onc.1201694. View

17.

Struhl G, Adachi A . Nuclear access and action of notch in vivo. Cell. 1998; 93(4):649-60. DOI: 10.1016/s0092-8674(00)81193-9. View

18.

Schroeter E, Kisslinger J, Kopan R . Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature. 1998; 393(6683):382-6. DOI: 10.1038/30756. View

19.

Sakai T, Taniguchi Y, Tamura K, Minoguchi S, Fukuhara T, Strobl L . Functional replacement of the intracellular region of the Notch1 receptor by Epstein-Barr virus nuclear antigen 2. J Virol. 1998; 72(7):6034-9. PMC: 110408. DOI: 10.1128/JVI.72.7.6034-6039.1998. View

20.

Shelly L, Fuchs C, Miele L . Notch-1 inhibits apoptosis in murine erythroleukemia cells and is necessary for differentiation induced by hybrid polar compounds. J Cell Biochem. 1999; 73(2):164-75. DOI: 10.1002/(sici)1097-4644(19990501)73:2<164::aid-jcb3>3.0.co;2-0. View