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Figure 2. Intracerebral inoculation of JC virus in newborn Golden Syrian hamsters induces neural origin tumors. Eighty percent of newborn hamsters inoculated with JC virus succumb to neural origin neoplasms. The most prevalent, medulloblastoma, appears as a highly cellular, poorly differentiated tumor with evidence of high mitotic activity. Note the presence of neuroblastic (Homer Wright) rosettes. Original magnification, x400.

toma. This tumor was also PCR positive for the Mad-4 strain of JCV. Primer extension studies showed synthesis of early RNA for T-antigen, while T-antigen protein was demonstrated by Western blot analysis and within tumor cells by immunocytochemistry.

Drawing from the tendency of JCV to produce primitive neuronal tumors in animal models and the above associations of the virus with primary human CNS neoplasms, we have recently analyzed a retrospective series of human medulloblastomas for JCV DNA and T-antigen expression. Using formalin-fixed paraffin embedded surgical material, genomic DNA was isolated. PCR was performed with primers to amplify the N- and C-terminal regions of T-antigen and products were analyzed via Southern blot hybridizations with JCV-specific radiolabeled probes. Immunohistochemistry was also performed on 16 of the tumors with a monoclonal antibody to T-antigen. Age-matched autopsy cerebellar tissue was used for both PCR and immunohistochemical negative controls. Analysis of the PCR products demonstrated JCV-specific sequences in a majority of the specimens. T-antigen positive nuclei were found in several of the specimens tested with specific nuclear localization. Since the data from this study show both JCV DNA and T-antigen protein in a significant proportion of human medulloblastomas, they argue for a strong association of this polyomavirus with one of the most frequent malignancies in childhood.

The large T-antigen of JCV is comprised of 688 amino acids with 70% homology with the well-characterized SV40 large T-antigen. The structural composition of SV40 large T-antigen encompassing various functional domains and the conserved regions between S V40 and JCV T-antigen are shown in Fig. 4. Note that the most highly conserved domain among all polyomavirus T-antigens is the ATPase domain, which partially overlaps with the region important

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