Abstract

The long-term objective of these studies is to understand how retroviruses that do not possess oncogenes cause neoplastic diseases in a tissue-specific manner. An important requirement for murine leukemia virus (MLV) disease specificity is efficient replication in the target cell for transformation. The control of cell type-specific virus replication and its effect on the early stages of tumorigenesis are not well understood for MLVs that induce thymic lymphoma, such as the mink cell focus-forming (MCF) MLV. A major determinant of MCF lymphomagenicity and virus replication in thymocytes is the region in the long terminal repeat that is located downstream of the enhancer (DEN). The binding site in DEN for the transcription factor NF-kB is essential for the effect of DEN on viral pathogenicity.
Aim 1 includes experiments to identify the thymic cell type that is infected by wild type and mutant MCF13 MLVs that are missing either the complete DEN region of the LTR or the NF-kB site in DEN.
In Aim 2, inducible transcription factors that activate DEN will be identified to test the hypothesis that MLV infection of thymocytes results in cellular activation.
Aim 3 includes experiments to examine the effects of virus infection on the proliferation of the thymic target for transformation. Proliferation will be assessed by measuring the fraction of virus-infected cells in the S and G2/M phases of the cell cycle. Other indicators of thymic cell proliferation, such as cdk2 kinase activity, and the expression of genes such as IL-2 and IL-2R, and those involved in thymocyte apoptosis will be assayed.
In Aim 4, the viral genes that are responsible for thymocyte activation and/or proliferation will be identified by the construction of chimeric viruses. The results of these studies will contribute to an understanding of the control of retrovirus replication in the early stages of lymphomagenesis. They will further help elucidate the steps in T lymphocyte activation in nomal and malignant cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA044166-15
Application #
6172066
Study Section
Virology Study Section (VR)
Program Officer
Cole, John S
Project Start
1979-04-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2002-06-30
Support Year
15
Fiscal Year
2000
Total Cost
$217,418
Indirect Cost

  Institution

Name
Wayne State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202

  Publications

Yoshimura, Fayth K; Luo, Xixia; Zhao, Xiaoqing et al. (2008) Up-regulation of a cellular protein at the translational level by a retrovirus. Proc Natl Acad Sci U S A 105:5543-8
Zhao, Xiaoqing; Yoshimura, Fayth K (2008) Expression of murine leukemia virus envelope protein is sufficient for the induction of apoptosis. J Virol 82:2586-9
Yoshimura, Fayth K; Luo, Xixia (2007) Induction of endoplasmic reticulum stress in thymic lymphocytes by the envelope precursor polyprotein of a murine leukemia virus during the preleukemic period. J Virol 81:4374-7
Nanua, Suparna; Yoshimura, Fayth K (2004) Mink epithelial cell killing by pathogenic murine leukemia viruses involves endoplasmic reticulum stress. J Virol 78:12071-4
Nanua, Suparna; Yoshimura, Fayth K (2004) Differential cell killing by lymphomagenic murine leukemia viruses occurs independently of p53 activation and mitochondrial damage. J Virol 78:5088-96
Yoshimura, F K; Wang, T (2001) Role of the LTR region between the enhancer and promoter in mink cell focus-forming murine leukemia virus pathogenesis. Virology 283:121-31
Yoshimura, F K; Wang, T; Nanua, S (2001) Mink cell focus-forming murine leukemia virus killing of mink cells involves apoptosis and superinfection. J Virol 75:6007-15
Yoshimura, F K; Wang, T; Yu, F et al. (2000) Mink cell focus-forming murine leukemia virus infection induces apoptosis of thymic lymphocytes. J Virol 74:8119-26
Yoshimura, F K; Wang, T; Cankovic, M (1999) Sequences between the enhancer and promoter in the long terminal repeat affect murine leukemia virus pathogenicity and replication in the thymus. J Virol 73:4890-8
Chen, H; Yoshimura, F K (1998) Spacing between the enhancer and promoter of the long terminal repeat of a murine leukaemia retrovirus is required for transcriptional activation in T cells. J Gen Virol 79 ( Pt 5):1101-4

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