The murine gammaherpesvirus 68 v-cyclin gene is an oncogene that promotes cell cycle progression in primary lymphocytes.
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 (gammaHV68) viral cyclin (v-cyclin). The gammaHV68 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 gammaHV68 v-cyclin on cell cycle progression in primary lymphocytes and to determine if the gammaHV68 v-cyclin gene is an oncogene, we generated transgenic mice by using the lck proximal promoter to express the gammaHV68 v-cyclin in early T cells. Expression of the gammaHV68 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 gammaHV68 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, gammaHV68-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 gammaHV68-v-cyclin-transgenic mice developed high-grade lymphoblastic lymphoma between 3 and 12 months of age. We conclude that (i) the gammaHV68 v-cyclin is expressed as a leaky-late gene in lytically infected cells, (ii) expression of the gammaHV68 v-cyclin in thymocytes promotes cell cycle progression and inhibits normal T-cell differentiation, and (iii) the gammaHV68 v-cyclin gene is an oncogene.
van Dyk
L F
LF
Center for Immunology, Departments of Pathology and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Hess
J L
JL
Katz
J D
JD
Jacoby
M
M
Speck
S H
SH
Virgin HW
I V
IV
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics*; D018142:Gammaherpesvirinae / Q000235:genetics*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics; D008223:Lymphoma / Q000209:etiology; D051379:Mice; D008822:Mice, Transgenic; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D011817:Rabbits; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D013601:T-Lymphocytes / Q000502:physiology; D014764:Viral Proteins
D016213:Cyclins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014764:Viral Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)