Expression of the Myelin Basic Protein Gene in Transgenic Mice Expressing Human Neurotropic Virus, JCV, Early Protein

Haas, Susan; Haque, Nasreen S.; Beggs, Alan H.; Khalili, Kamel; Knobler, Robert L.; Small, J A

doi:10.1006/viro.1994.1325

Cited by 16 publications

(11 citation statements)

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“…Indeed, electron microscopy revealed a lack of myelin sheath surrounding axons of the spinal cord and the presence of noncompacted myelin in two independent lines of mice (Small et al, 1986a, b). Subsequent molecular studies have suggested that JCV T-antigen may directly affect myelin gene expression at the transcriptional level (Haas et al, 1994;Devireddy et al, 1996), while the possibility of an indirect effect from neighboring T-antigen expressing astrocytes has been suggested from the analysis of mouse polyoma virus T-antigen transgenic mice with dysmyelination (Baron- Van Evercooren et al, 1992). The dysmyelinating phenotype has been observed in several founder animals, but its severity has prevented their successful breeding.…”

Section: Transgenic Mouse Modelsmentioning

confidence: 99%

Human neurotropic polyomavirus, JCV, and its role in carcinogenesis

et al. 2003

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A number of recent studies have reported the detection of the ubiquitous human polyomavirus, JC virus (JCV), in samples derived from several types of neural as well as non-neural human tumors. The human neurotropic JCV was first identified as the etiologic agent of the fatal demyelinating disease, progressive multifocal leukoencephalopathy, which usually occurs in individuals with defects in cell-mediated immunity, including AIDS. However, upon mounting evidence of the oncogenic potential of the viral regulatory protein, T-antigen, and JCV's oncogenecity in a broad range of animal models, studies were initiated to determine its potential involvement in human carcinogenesis. Initially, the most frequently observed tumors in rodent models, including medulloblastoma, astrocytoma, glioblastoma, and other neural-origin tumors were analysed. These studies were followed by analysis of non-neural tumors such as colorectal carcinomas. In a subset of each tumor type examined, JC viral genomic DNA sequences could be detected by PCR and confirmed by Southern blot hybridization or direct sequencing. In a smaller subset of the tumors, the expression of T-antigen was observed by immunohistochemical analysis. Owing to the established functions of T-antigen including its ability to interact with tumor suppressor proteins such as Rb and p53, and its ability to influence chromosomal stability, potential mechanisms of JCV T-antigen-mediated cellular dysregulation are discussed. Further, as increasing evidence suggests that T-antigen is not required for maintenance of a transformed phenotype, a hit-and-run model for T-antigen-induced transformation is proposed.

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Section: Transgenic Mouse Modelsmentioning

confidence: 99%

Human neurotropic polyomavirus, JCV, and its role in carcinogenesis

et al. 2003

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“…Although the JCV genome has been detected in several tissues (14,15,22,33), replication of the viral genome is seen predominantly in glial cells of the central nervous system (CNS) (8). Several lines of studies, including in vitro transcription of the viral genome (1,2), transfection of various cells with recombinant plasmids containing the viral regulatory sequence (16,25,46), and creation of transgenic animals containing the JCV promoter sequence (16,23,41), have established that the tissuespecific replication of the viral genome is due to the transcriptional activity of the viral promoter, which is more efficient in CNS cells. Therefore, much effort has been directed toward analysis of the JCV regulatory sequence and identification of host proteins which, upon interaction with their target sequence within the promoter, confer specificity to viral gene transcription.…”

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confidence: 99%

Reciprocal Interaction between Two Cellular Proteins, Purα and YB-1, Modulates Transcriptional Activity of JCV_CY in Glial Cells

Safak

Gallia

Khalili

1999

Molecular and Cellular Biology

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Cross communication between regulatory proteins is an important event in the control of eukaryotic gene transcription. Here we have examined the structural and functional interaction between two cellular regulatory proteins, YB-1 and Puralpha, on the 23-bp sequence element derived from the enhancer-promoter of the human polyomavirus JCV. YB-1 and Puralpha are single-stranded DNA binding proteins which recognize C/T- and GC/GA-rich sequences, respectively. Results from band shift studies demonstrated that while both proteins interact directly with their DNA target sequences within the 23-bp motif, each protein can regulate the association of the other one with the DNA. Affinity chromatography and coimmunoprecipitation provide evidence for a direct interaction between Puralpha and YB-1 in the absence of the DNA sequence. Ectopic expression of YB-1 and Puralpha in glial cells synergistically stimulated viral promoter activity via the 23-bp sequence element. Results from mutational studies revealed that residues between amino acids 75 and 203 of YB-1 and between amino acids 85 and 215 of Puralpha are important for the interaction between these two proteins. Functional studies with glial cells indicated that the region within Puralpha which mediates its association with YB-1 and binding to the 23-bp sequence is important for the observed activation of the JCV promoter by the Puralpha and YB-1 proteins. The results of this study suggest that the cooperative interaction between YB-1 and Puralpha mediates the synergistic activation of the human polyomavirus JCV genome by these cellular proteins. The importance of these findings for cellular and viral genes which are regulated by Puralpha and YB-1 is discussed.

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“…Transgenic mice harboring the regulatory region and T antigen of JCV exhibit immature oligodendrocytes, hypomyelination, and dysmyelination (18)(19)(20). Thus, it seems that JCV may cause demyelination directly through the cytolytic infection of oligodendrocytes and indirectly by T antigen-mediated inhibition of myelin production.…”

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Detection of JC virus DNA sequence and expression of the viral oncoprotein, tumor antigen, in brain of immunocompetent patient with oligoastrocytoma.

Rencic

Gordon

Otte

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

115

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We describe molecular and clinical findings in an immunocompetent patient with an oligoastrocytoma and the concomitant presence of the human papovavirus, JC virus (JCV), which is the etiologic agent ofthe subacute, debilitating demyelinating disease, progressive multifocal leukoencephalopathy. Histologic review revealed a glial neoplasm consisting primarily of a moderately cellular oligodendroglioma with distinct areas of a fibrillary astrocytoma. Immunohistochemical analysis revealed nuclear staining of tumor cells with antibodies against the viral oncoprotein [tumor antigen (T antigen)], the proliferation marker (Ki67), and the cellular proliferation regulator (p53). Using primers specific to the JCV control region, PCR yielded amplified DNA that was identical to the control region of the Mad-4 strain of the virus. PCR analysis demonstrated the presence of the genome for the viral oncoprotein, T antigen, and results from primer extension studies revealed synthesis of the viral early RNA for T antigen in the tumor tissues. The presence of viral T antigen in the tumor tissue was further demonstrated by immunoblot assay. To our knowledge, this is the first report of the presence of JCV DNA, RNA, and T antigen in tissue in which viral T antigen is localized to tumor cell nuclei and suggests the possible association of JCV with some glial neoplasms.

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Expression of the Myelin Basic Protein Gene in Transgenic Mice Expressing Human Neurotropic Virus, JCV, Early Protein

Cited by 16 publications

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Human neurotropic polyomavirus, JCV, and its role in carcinogenesis

Human neurotropic polyomavirus, JCV, and its role in carcinogenesis

Reciprocal Interaction between Two Cellular Proteins, Purα and YB-1, Modulates Transcriptional Activity of JCV_CY in Glial Cells

Detection of JC virus DNA sequence and expression of the viral oncoprotein, tumor antigen, in brain of immunocompetent patient with oligoastrocytoma.

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Expression of the Myelin Basic Protein Gene in Transgenic Mice Expressing Human Neurotropic Virus, JCV, Early Protein

Cited by 16 publications

References 0 publications

Human neurotropic polyomavirus, JCV, and its role in carcinogenesis

Human neurotropic polyomavirus, JCV, and its role in carcinogenesis

Reciprocal Interaction between Two Cellular Proteins, Purα and YB-1, Modulates Transcriptional Activity of JCVCY in Glial Cells

Detection of JC virus DNA sequence and expression of the viral oncoprotein, tumor antigen, in brain of immunocompetent patient with oligoastrocytoma.

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Reciprocal Interaction between Two Cellular Proteins, Purα and YB-1, Modulates Transcriptional Activity of JCV_CY in Glial Cells