The murine gammaherpesvirus 68 v-cyclin gene is an oncogene that promotes cell cycle progression in primary lymphocytes

Linda F. Van Dyk, Jay L. Hess, Jonathan D. Katz, Meagan Jacoby, Samuel H. Speck, Herbert W. Virgin IV

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Several gammaherpesviruses contain open reading frames encoding proteins homologous to mammalian D-type cyclins. In this study, we analyzed the expression and function of the murine gammaherpesvirus 68 (γHV68) viral cyclin (v-cyclin). The γHV68 v-cyclin gene was expressed in lytically infected fibroblasts as a leaky-late mRNA of approximately 0.9 kb encoding a protein of approximately 25 kDa. To evaluate the effect of the γHV68 v- cyclin on cell cycle progression in primary lymphocytes and to determine if the γHV68 v-cyclin gene is an oncogene, we generated transgenic mice by using the lck proximal promoter to express the γHV68 v-cyclin in early T cells. Expression of the γHV68 v-cyclin significantly increased the number of thymocytes in cell culture, as determined by measuring both DNA content and incorporation of 5-bromo-2-deoxyuridine following in vivo pulse- labeling. Expression of the γHV68 v-cyclin interfered with normal thymocyte maturation, as shown by increased numbers of CD4+ CD8+ double-positive thymocytes and decreased numbers of CD4+ or CD8+ single-positive and T- cell-receptor-bright thymocytes and splenocytes in transgenic mice. Despite increased numbers of cycling thymocytes, γHV68-v-cyclin-transgenic mice did not have proportionately increased thymocyte numbers, and staining by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling demonstrated increased apoptosis in the thymi of v-cyclin-transgenic mice. Fifteen of 38 γHV68-v-cyclin-transgenic mice developed high-grade lymphoblastic lymphoma between 3 and 12 months of age. We conclude that (i) the γHV68 v-cyclin is expressed as a leaky-late gene in lytically infected cells, (ii) expression of the γHV68 v-cyclin in thymocytes promotes cell cycle progression and inhibits normal T-cell differentiation, and (iii) the γHV68 v-cyclin gene is an oncogene.

Original languageEnglish (US)
Pages (from-to)5110-5122
Number of pages13
JournalJournal of virology
Volume73
Issue number6
DOIs
StatePublished - 1999

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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