Abstract/Details

Identification and characterization of cellular proteins regulating transcription of human neurotropic virus, JCV


1996 1996

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Abstract (summary)

Progressive multifocal leukoencephalopathy (PML) is a neurodegenerative disease that in years past was considered quite rare. The human JC polyomavirus (TCV) was found to cause this demyelinating condition in human central nervous system (CNS) by ZuRhein and Chou (1965), and Silverman and Rubinstein (1965). Electron micrographs of brain sections from a PML patient with PML revealed particles similiar to SV40. These could not then be isolated for lack of a proper culture system. JCV was first isolated from the brain of a PML patient in 1971 by Padgett and colleagues, who inoculated cultures of human fetal brain cells with extracts of diseased tissue. JCV was subsequently found in the brains of other PML patients, and is considered the etiological agent of this disease.

Most patients have a primary JCV infection by before adulthood; this presumably lies dormant as an archetypic viral genome in various tissues. Reactivation of the latent virus can occur with prolonged immunosuppression, leading to opportunistic infection, cytolytic destruction of the myelin-producing cells in the CNS, and demyelination.

JCV exhibits a restricted specificity for glial cells; in tissue culture it propagates only in primary human fetal glial cells. The highest transcriptional level of viral genes is in glial-derived cells. The tissue tropism of JCV is controlled by the plastic noncoding region, which serves as the promoter/enhancer for bidirectionally regulating the expression of viral early and late genes, and as the origin for DNA replication.

The central region of the JCV promoter/enhancer, designated the B-domain, plays an important role in determining the active transcription of viral genes in glial cells. This study focuses on identifying the cellular proteins, YB-1, Pur $\alpha$, and GF-1, which interact with the key region of the JC viral promoter and stimulate transcriptional activity, directing the viral tissue-specific tropism and lytic cycle progression.

Results of the study characterize the DNA binding activity of YB-1 and Pur $\alpha$ to their target sequences; these are influenced by each other in the presence and absence of the viral regulatory protein, T antigen. Further transient transfection experiments demonstrate that regulation of the DNA binding activity of these cellular proteins may be involved in modulating their transactivation activity. These interactions between cellular proteins YB-1 and Pur $\alpha$ with JCV T antigen coordinate the determinate early and late promoter activity of JCV in the progression of its lytic cycle. A working model is proposed on the basis of these observations; it provides ample opportunity for revision on further characterization of the interacting viral and cellular factors.

The study of GF-1 in the regulation of JCV transcription is confirmed and extended by using the full length cDNA clone, S$\mu$bp-2, which binds to the B-domain and mediates the activation of the JCV late promoter. S$\mu$bp-2 enhances the transactivation of the viral late promoter induced by JCV T antigen in an additive manner. The possible involvement of S$\mu$bp-2 in the JCV infectious cycle, especially in DNA replication, is discussed with regard to DNA binding ability, helicase activity, and the possibility of nuclear localization.

Indexing (details)


Subject
Microbiology;
Molecular biology;
Neurology
Classification
0410: Microbiology
0307: Molecular biology
0317: Neurology
Identifier / keyword
Biological sciences
Title
Identification and characterization of cellular proteins regulating transcription of human neurotropic virus, JCV
Author
Chen, Nancie Nien-Tsyr
Number of pages
116
Publication year
1996
Degree date
1996
School code
0272
Source
DAI-B 57/09, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780591102499, 0591102498
Advisor
Khalili, Kamel
University/institution
Thomas Jefferson University
University location
United States -- Pennsylvania
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
9703673
ProQuest document ID
304314507
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304314507
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