title: LMP1 of Epstein-Barr virus induces proliferation of primary mouse embryonic fibroblasts and cooperatively transforms the cells with a p16-insensitive CDK4 oncogene.
abstract: The latent membrane protein LMP1 of Epstein-Barr virus (EBV) is often present in EBV-associated malignancies including nasopharyngeal carcinoma and Hodgkin's lymphoma. Previous work demonstrates that the LMP1 gene of EBV is sufficient to transform certain established rodent fibroblast cell lines and to induce the tumorigenicity of some human epithelial cell lines. In addition, LMP1 plays pleiotropic roles in cell growth arrest, differentiation, and apoptosis, depending on the background of the target cells. To examine the roles of LMP1 in cell proliferation and growth regulation in primary culture cells, we constructed a recombinant retrovirus containing an LMP1 gene. With this retrovirus, LMP1 was shown to stimulate the proliferation of primary mouse embryonic fibroblasts (MEF cells). It has a mitogenic activity for MEF cells, as demonstrated by an immediate induction of cell doubling time. In addition, it significantly extends the passage number of MEF cells to more than 30 after retroviral infection, compared with less than 5 for uninfected MEF cells. Furthermore, LMP1 cooperates with a p16-insensitive CDK4(R24C) oncogene in transforming MEF cells. Our results provide the first evidence of the abilities of the LMP1 gene, acting alone, to effectively induce the proliferation of primary MEF cells and of its cooperativity with another cellular oncogene in transforming primary cells.
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.forename: J S
authors.initials: JS
authors.lastname: Sham
authors.forename: M H
authors.initials: MH
authors.lastname: Ng
authors.forename: S W
authors.initials: SW
authors.lastname: Tsao
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.forename: S W
authors.initials: SW
authors.lastname: Lowe
authors.forename: L
authors.initials: L
authors.lastname: Cao
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology; D005822:Genetic Vectors / Q000235:genetics; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D012190:Retroviridae / Q000235:genetics; D019098:Telomerase / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D009856:Oncogene Proteins, Viral; D011518:Proto-Oncogene Proteins; D014763:Viral Matrix Proteins; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D019098:Telomerase