Pituitary neoplasia induced by expression of human neurotropic polyomavirus, JCV, early genome in transgenic mice

Gordon, Jennifer; Valle, Luis Del; Otte, Jessica; Khalili, Kamel

doi:10.1038/sj.onc.1203849

Cited by 58 publications

(42 citation statements)

References 22 publications

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“…This observation is consistent with previous studies in JCV transgenic mice, which were created by JCV-early genes. Interestingly, immunohistochemical studies of various tumors induced in these transgenic animals revealed that a subset of tumor cells exhibited viral large T antigen expression, 8,9 suggesting that expression of JCV tumor antigen is negatively regulated by host factors in a specific portion of these tumors. In addition, subcutaneous inoculation of the large T antigen positive cells, BsB8, in the flanks of nude mice resulted in rapid tumor development, while large T antigen negative cells did not proliferate significantly in nude mice, suggesting that large T antigen expression contributes to the growth of these tumors.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 Transgenic animals expressing the JCV-early genome under the control of the JCV promoter develop neural-origin tumors including adrenal neuroblastoma, medulloblastoma, malignant peripheral nerve sheath tumors, and pituitary adenomas. [6][7][8][9] The oncogenic potential of JCV is strongly related to the expression of viral large and small tumor antigens. Ample evidence suggests that the mechanism of JCV-mediated transformation relies on the sequestration and suppression of the tumor suppressor proteins, p53 and the pRb family, by the viral large T antigen.…”

Section: Introductionmentioning

confidence: 99%

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Extinction of Tumor Antigen Expression by SF2/ASF in JCV-Transformed Cells

et al. 2011

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The human neurotropic polyomavirus JC (JCV) induces a broad range of neural-origin tumors in experimental animals and has been repeatedly detected in several human cancers, most notably neural crest-origin tumors including medulloblastomas and glioblastomas. The oncogenic activity of JCV is attributed to the viral early gene products, large T and small t antigens, as evident by results from in vitro cell culture and in vivo animal studies. Recently, we have shown that alternative splicing factor, SF2/ASF, has the capacity to exert a negative effect on transcription and splicing of JCV genes in glial cells through direct association with a specific DNA motif within the viral promoter region. Here, we demonstrate that SF2/ASF suppresses large T antigen expression in JCV-transformed tumor cell lines, and the expression of SF2/ASF in such tumor cells thereby inhibits the transforming capacity of the viral tumor antigens. Moreover, down-regulation of SF2/ASF in viral-transformed tumor cell lines induces growth and proliferation of the tumor cells. Mapping analysis of the minimal peptide domain of SF2/ASF responsible for JCV promoter silencing and tumor suppressor activity suggests that amino acid residues 76 to 100 of SF2/ASF are functionally sufficient to suppress the growth of the tumor cells. These observations demonstrate a role for SF2/ASF in JCVmediated cellular transformation and provide a new avenue of research to pathogenic mechanisms of JCV-induced tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Extinction of Tumor Antigen Expression by SF2/ASF in JCV-Transformed Cells

et al. 2011

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“…Due to restrictions in lytic infection believed to occur upon infection of human polyomaviruses in rodent models, the use of early gene constructs lacking the late gene sequences may recapitulate the situation seen in abortive infections in human. SV40 transgenic mice have developed choroid plexus papillomas (Brinster et al, 1984;Messing et al, 1988;Van Dyke et al, 1987), whereas JCV transgenic mouse lines have developed medulloblastomas, peripheral neuroectodermal origin tumors including adrenal neuroblastomas and primitive mesenteric tumors, pituitary adenomas, and malignant peripheral nerve sheath tumors (Franks et al, 1996;Gordon et al, 2000;Gordon et al, unpublished observations, Krynska et al, 1999b;Small et al, 1986). …”

Section: Tumors Induced In Experimental Animal Modelsmentioning

confidence: 99%

Brain Tumors and Polyomaviruses

2003

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“…Intravenous or intracranial inoculation of JCV into experimental animals has been found to cause astrocytomas, glioblastomas, neuroblastomas and medulloblastomas (1). In addition, transgenic mice expressing the JCV T antigen exhibit a 50% incidence of pituitary adenomas by 1 year of age and some of the mice develop malignant peripheral nerve sheath tumors (1,8). In recent years, the presence of JCV has been suggested to correlate with various types of human neoplasms, including tongue, pharyngeal, gastric, esophageal, colorectal, anal and prostatic cancer, brain tumors and lung carcinomas B (9-21).…”

Section: Introductionmentioning

confidence: 99%