scholarly journals The Murine Gammaherpesvirus 68 v-Cyclin Gene Is an Oncogene That Promotes Cell Cycle Progression in Primary Lymphocytes

1999 ◽  
Vol 73 (6) ◽  
pp. 5110-5122 ◽  
Author(s):  
Linda F. van Dyk ◽  
Jay L. Hess ◽  
Jonathan D. Katz ◽  
Meagan Jacoby ◽  
Samuel H. Speck ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Transgenic Mice ◽  
Cell Cycle Progression ◽  
Proximal Promoter ◽  
Cycle Progression ◽  
Murine Gammaherpesvirus ◽  
Cyclin Gene ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

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 lckproximal 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.

scholarly journals The Murine Gammaherpesvirus 68 v-Cyclin Gene Is an Oncogene That Promotes Cell Cycle Progression in Primary Lymphocytes

1999 ◽  
Vol 73 (8) ◽  
pp. 7098-7098 ◽  
Author(s):  
Linda F. Van Dyk ◽  
Jay L. Hess ◽  
Jonathan D. Katz ◽  
Meagan Jacoby ◽  
Samuel H. Speck ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Murine Gammaherpesvirus ◽  
Cyclin Gene ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

scholarly journals Two Kinetic Patterns of Epitope-Specific CD8 T-Cell Responses following Murine Gammaherpesvirus 68 Infection

2010 ◽  
Vol 84 (6) ◽  
pp. 2881-2892 ◽  
Author(s):  
Michael L. Freeman ◽  
Kathleen G. Lanzer ◽  
Tres Cookenham ◽  
Bjoern Peters ◽  
John Sidney ◽  
...  
Keyword(s):  
T Cell ◽  
Expression Patterns ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Immune Control ◽  
Murine Gammaherpesvirus ◽  
Cell Responses ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Murine gammaherpesvirus 68 (γHV68) provides an important experimental model for understanding mechanisms of immune control of the latent human gammaherpesviruses. Antiviral CD8 T cells play a key role throughout three separate phases of the infection: clearance of lytic virus, control of the latency amplification stage, and prevention of reactivation of latently infected cells. Previous analyses have shown that T-cell responses to two well-characterized epitopes derived from ORF6 and ORF61 progress with distinct kinetics. ORF6487-specific cells predominate early in infection and then decline rapidly, whereas ORF61524-specific cells continue to expand through early latency, due to sustained epitope expression. However, the paucity of identified epitopes to this virus has limited our understanding of the overall complexities of CD8 T-cell immune control throughout infection. Here we screened 1,383 predicted H-2b-restricted peptides and identified 33 responses, of which 21 have not previously been reported. Kinetic analysis revealed a spectrum of T-cell responses based on the rapidity of their decline after the peak acute response that generally corresponded to the expression patterns of the two previously characterized epitopes. The slowly declining responses that were maintained during latency amplification proliferated more rapidly and underwent maturation of functional avidity over time. Furthermore, the kinetics of decline was accelerated following infection with a latency-null mutant virus. Overall, the data show that γHV68 infection elicits a highly heterogeneous CD8 T-cell response that segregates into two distinctive kinetic patterns controlled by differential epitope expression during the lytic and latency amplification stages of infection.

scholarly journals Mononucleosis and Antigen-Driven T Cell Responses Have Different Requirements for Interleukin-2 Signaling in Murine Gammaherpesvirus Infection

2010 ◽  
Vol 84 (20) ◽  
pp. 10923-10927 ◽  
Author(s):  
Michael Molloy ◽  
Weijun Zhang ◽  
Edward Usherwood
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
T Cell Response ◽  
Long Term Memory ◽  
Murine Gammaherpesvirus ◽  
Cell Responses ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Interleukin-2 (IL-2) has been implicated as being necessary for the optimal formation of primary CD8+ T cell responses against various pathogens. Here we have examined the role that IL-2 signaling plays in several aspects of a CD8+ T cell response against murine gammaherpesvirus 68 (MHV-68). Exposure to MHV-68 causes a persistent infection, along with infectious mononucleosis, providing a model for studying these processes in mice. Our study indicates that CD25 is necessary for optimal expansion of the antigen-specific CD8+ T cell response but not for the long-term memory response. Contrastingly, IL-2 signaling through CD25 is absolutely required for CD8+ T cell mononucleosis.

Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27kip1

Blood ◽  
2001 ◽  
Vol 98 (5) ◽  
pp. 1524-1531 ◽  
Author(s):  
Joao T. Barata ◽  
Angelo A. Cardoso ◽  
Lee M. Nadler ◽  
Vassiliki A. Boussiotis
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Cell Cycle Progression ◽  
Lymphoblastic Leukemia ◽  
Cyclin Dependent Kinase ◽  
Malignant Cells ◽  
Cycle Progression ◽  
Interleukin 7 ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Immature Thymocytes

In normal T-cell development interleukin-7 (IL-7) functions as an antiapoptotic factor by regulating bcl-2 expression in immature thymocytes and mature T cells. Similar to what occurs in normal immature thymocytes, prevention of spontaneous apoptosis by IL-7 in precursor T-cell acute lymphoblastic leukemia (T-ALL) cells correlates with up-regulation of bcl-2. IL-7 is also implicated in leukemogenesis because IL-7 transgenic mice develop lymphoid malignancies, suggesting that IL-7 may regulate the generation and expansion of malignant cells. This study shows that in the presence of IL-7, T-ALL cells not only up-regulated bcl-2 expression and escaped apoptosis but also progressed in the cell cycle, resulting in sequential induction of cyclin D2 and cyclin A. Down-regulation of p27kip1 was mandatory for IL-7–mediated cell cycle progression and temporally coincided with activation of cyclin-dependent kinase (cdk)4 and cdk2 and hyperphosphorylation of Rb. Strikingly, forced expression of p27kip1 in T-ALL cells not only prevented cell cycle progression but also reversed IL-7–mediated up-regulation of bcl-2 and promotion of viability. These results show for the first time that a causative link between IL-7–mediated proliferation and p27kip1 down-regulation exists in malignant T cells. Moreover, these results suggest that p27kip1 may function as a tumor suppressor gene not only because it is a negative regulator of cell cycle progression but also because it is associated with induction of apoptosis of primary malignant cells.

scholarly journals HCV core/gC1qR interaction arrests T cell cycle progression through stabilization of the cell cycle inhibitor p27Kip1

Virology ◽  
2003 ◽  
Vol 314 (1) ◽  
pp. 271-282 ◽  
Author(s):  
Zhi Qiang Yao ◽  
Audrey Eisen-Vandervelde ◽  
Suma Ray ◽  
Young S Hahn
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Cell Cycle Inhibitor

OSI-027, a Dual TORC1/TORC2 Inhibitor, Induces Bim- and Puma-Mediated Apoptosis In Lymphoid Malignancy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 970-970 ◽  
Author(s):  
Andrea E. Wahner Hendrickson ◽  
Mamta Gupta ◽  
Seongseok Yun ◽  
Jennifer C. Shing ◽  
Paula A. Schneider ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Cell Cycle Progression ◽  
Mitochondrial Pathway ◽  
Lymphoid Cells ◽  
Jurkat Cells ◽  
Lymphoid Malignancy ◽  
Cycle Progression ◽  
Advisory Boards ◽  
Wide Range

Abstract Abstract 970 The mammalian target of rapamycin, mTOR, is a highly conserved serine/threonine kinase known to play a role in regulating mRNA translation, cell cycle progression, cell proliferation and apoptosis. As a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, mTOR is a component of two distinct complexes, TORC1 and TORC2. While TORC1 facilitates cell cycle progression from G1 into S phase by phosphorylating p70S6 kinase and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), TORC2 catalyzes the activating phosphorylation of Akt on Ser473, providing a feedback loop for further activation of mTOR. Phase II trials have shown activity of the TORC1-selective inhibitor rapamycin and its analogs in a wide range of lymphoma subtypes. The purpose of this study was to evaluate the anti-proliferative and pro-apoptotic effects of the dual TORC1/TORC2 inhibitor OSI-027 in human neoplastic lymphoid cells in vitro. MTS assays demonstrated that OSI-027 inhibited proliferation in a wide range of lymphoid lines, including SeAx (Sezary syndrome), DoHH2 (large cell lymphoma), RL (follicular lymphoma) and Jurkat (T cell ALL), as well as clinical lymphoma and T cell ALL samples, with IC50 values ranging from 0.078 to 10 μM. Propidium iodide staining followed by flow cytometry for subdiploid cells revealed induction of apoptosis within 48 h of treatment with OSI-027 (but not rapamycin) in SeAx, DoHH2, and Jurkat cells. Examination of Jurkat variants with alterations in key proteins involved in the death receptor versus mitochondrial pathway revealed diminished apoptotic responses to OSI-027 when Bcl-2 was overexpressed or caspase 9 was silenced, indicating involvement of the mitochondrial pathway. Immunoblotting for Bcl-2 family members revealed upregulation of Bim and Puma after a 48-hour exposure to OSI-027 but not rapamycin. This upregulation was also seen at the mRNA level, with a 12- to 20-fold increase in Puma mRNA and 4- to 12-fold induction of Bim mRNA. Small interfering RNA (siRNA)-mediated knockdown of Bim and Puma significantly diminished the apoptotic response to OSI-027. Because the Foxo3a transcription factor has been implicated in Bim and Puma expression and is known to be activated when Akt is inhibited, we next examined whether Bim and Puma induction was Foxo3a-dependent. Luciferase reporter assays showed that OSI-027 activated the full-length Puma and Bim promoters and that this activation was diminished when the Foxo3a binding sites were deleted or mutated. In addition, OSI-027 induced nuclear translocation of Foxo3a, while Foxo3a siRNA diminished OSI-027-induced apoptosis in Jurkat cells. Collectively, these results indicate that OSI-027 inhibits proliferation and induces apoptosis in a wide range of neoplastic lymphoid cells through a process that involves Foxo3a-mediated upregulation of Bim and Puma. These results also suggest that dual inhibition of TORC1 and TORC2 may be an effective treatment strategy in lymphoid malignancy. Disclosures: Barr: OSI Pharmaceuticals: Employment. Witzig:Novartis and Celgene: Patents & Royalties, Research Funding, Served on advisory boards with Novartis and Celgene – both uncompensated with compensation to Mayo Clinic.

Sign in / Sign up

Export Citation Format

Share Document