Epstein-Barr virus nuclear protein 2 is a critical determinant for tumor growth in SCID mice and for transformation in vitro.
Injection of Epstein-Barr virus (EBV)-transformed human lymphoblastoid B cells into immunodeficient SCID mice results in the appearance of rapidly growing, fatal human B-cell tumors. To evaluate the role of EBV nuclear protein 2 (EBNA-2) in this process, we generated lymphoblastoid cell lines transformed by several EBV mutants which were identical except for deletions in the EBNA-2 gene (J. I. Cohen, F. Wang, and E. Kieff, J. Virol. 65:2545-2554, 1991). These cell lines were injected intraperitoneally into SCID mice, and the interval until tumor detection was determined. Cell lines transformed with EBV type 1 (strain W91) or with EBV type 2 (strain P3HR-1) with an inserted type 1 EBNA-2 gene grew at the same rapid rate, indicating the potential importance of EBNA-2 for tumor formation in vivo. Cell lines derived from three different EBV mutants with deletions in the amino half of EBNA-2 produced tumors more slowly than cell lines transformed by wild-type W91 virus. In contrast, a cell line transformed with an EBV mutant with a deletion in the carboxy terminus of EBNA-2 grew more rapidly than cell lines transformed by wild-type virus. EBV mutants with deletions in the amino half of EBNA-2 had had reduced transforming activity in vitro, while the carboxy-terminal EBNA-2 mutant had had transforming activity greater than or equal to that of the wild type. These data indicate that EBNA-2 plays a critical role both for B-cell tumor growth in SCID mice and for B-lymphocyte transformation in vitro.
Cohen
J I
JI
Medical Virology Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892.
Picchio
G R
GR
Mosier
D E
DE
D000818:Animals; D000956:Antigens, Viral / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015139:Blotting, Southern; D002472:Cell Transformation, Viral; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019309:Epstein-Barr Virus Nuclear Antigens; D017353:Gene Deletion; D016679:Genome, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D008970:Molecular Weight; D012091:Repetitive Sequences, Nucleic Acid; D015533:Transcriptional Activation; D014412:Tumor Virus Infections / Q000382:microbiology / Q000473:pathology*; D014759:Viral Envelope Proteins / Q000032:analysis / Q000235:genetics; D014763:Viral Matrix Proteins
D000956:Antigens, Viral; D004273:DNA, Neoplasm; D004279:DNA, Viral; D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D008565:Membrane Proteins; D014759:Viral Envelope Proteins; D014763:Viral Matrix Proteins