JCV is a human polyoma virus which virus which has been isolated from the brain of patients with chronic demyelinating disease, progressive multifocal leukoencephalopathy (PML). This oncogenic virus is associated with the development of brain tumors including glioblastomas, medulloblastomas, neuroblastomas and other tumor of neural origin. JCV exhibits a highly specific host range and tissue specificity. In vitro, JCV grows exclusively in primary human fetal glial cells. Several studies have shown that the restricted host range of JCV to brain tissue in cell culture is determined at the transcriptional level. However, the mechanisms that govern tissue-specific transcription of this virus in brain cells remain unknown.
The aim of the research outlined in this proposal is to define the mechanisms by which the JC virus genome is regulated transcriptionally in a tissue-specific manner. The experimental design includes: (1) identification of the cis-acting transcriptional control elements of the viral genome; (2) characterization and purification of the trans-acting regulatory proteins from permissive cells and tissue that by interacting with the cis-acting sequences that control transcription of the viral genome; (3) cloning of the gene encoding the regulatory proteins, and large- scale production of these proteins for detailed structural/functional studies. The information gained from these manipulations and analyses should increase understanding of the mechanisms that modulate transcription of the viral genes in neural cells and the tumorgenicity of this virus in brain.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29CA047996-01
Application #
3459090
Study Section
Experimental Virology Study Section (EVR)
Project Start
1988-07-01
Project End
1993-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Ranganathan, P N; Khalili, K (1993) The transcriptional enhancer element, kappa B, regulates promoter activity of the human neurotropic virus, JCV, in cells derived from the CNS. Nucleic Acids Res 21:1959-64
Taylor, J P; Kundu, M; Khalili, K (1993) TAR-independent activation of HIV-1 requires the activation domain but not the RNA-binding domain of Tat. Virology 195:780-5
Chowdhury, M; Kundu, M; Khalili, K (1993) GA/GC-rich sequence confers Tat responsiveness to human neurotropic virus promoter, JCVL, in cells derived from central nervous system. Oncogene 8:887-92
Taylor, J P; Cupp, C; Diaz, A et al. (1992) Activation of expression of genes coding for extracellular matrix proteins in Tat-producing glioblastoma cells. Proc Natl Acad Sci U S A 89:9617-21
Tada, H; Khalili, K (1992) A novel sequence-specific DNA-binding protein, LCP-1, interacts with single-stranded DNA and differentially regulates early gene expression of the human neurotropic JC virus. J Virol 66:6885-92
Chowdhury, M; Taylor, J P; Chang, C F et al. (1992) Evidence that a sequence similar to TAR is important for induction of the JC virus late promoter by human immunodeficiency virus type 1 Tat. J Virol 66:7355-61
Taylor, J P; Pomerantz, R; Bagasra, O et al. (1992) TAR-independent transactivation by Tat in cells derived from the CNS: a novel mechanism of HIV-1 gene regulation. EMBO J 11:3395-403
Tada, H; Lashgari, M S; Khalili, K (1991) Regulation of JCVL promoter function: evidence that a pentanucleotide ""silencer"" repeat sequence AGGGAAGGGA down-regulates transcription of the JC virus late promoter. Virology 180:327-38
Kerr, D; Khalili, K (1991) A recombinant cDNA derived from human brain encodes a DNA binding protein that stimulates transcription of the human neurotropic virus JCV. J Biol Chem 266:15876-81
Chowdhury, M; Taylor, J P; Tada, H et al. (1990) Regulation of the human neurotropic virus promoter by JCV-T antigen and HIV-1 tat protein. Oncogene 5:1737-42

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