Nearly 70% of the adult population is infected with the JC neurotropic polyoma virus. In immunocompromised individuals this results in the development of the fatal neurodegenerative disease, progressive multifocal leukoencephalopathy (PML). In several experimental animals, infection of brain with JCV results in the formation of glioblastoma. Intracerebral inoculation of golden Syrian hamsters with JCV preceded the development in a great (80%) proportion of these animals of malignant brain tumors or peripheral neuroblastomas. A similar phenotype of brain tumors was seen upon the inoculation of owl monkeys with JCV, with the development of malignant astrocytomas expressing the viral T-antigen. The ability of JCV to cause tumors in these animals is well documented. The JC virus is capable of transforming primary hamster brain cells and primary human fetal glial cells. The transforming ability of JCV is attributed to its multipotent early gene product, the large T-antigen. In vitro studies have indicated that the JCV T-antigen is capable of interaction with the tumor suppressor genes, p53, pRb, p107, and p130. T-antigen is thought to functionally inactivate these tumor suppressor genes in glial cells, resulting in the formation of glial tumors in these animals. In this proposal, we will use our unique JCV-injected newborn hamster system to study in vivo the molecular mechanisms involved in the formation and progression of brain tumors through the disruption of the key regulatory factors of the cell cycle. We will examine the role of the Rb family and how its interaction with JCV T-antigen results in the disruption of the regulatory processes of the cell cycle and allows for neoplastic transformation and tumorigenesis. In particular, we will focus on the pRb2/p130, the Rb family member first cloned in our laboratory and exhibits growth suppressive properties in glioma cells. Specifically we will: (1) Determine the biological importance of pRb2/p130 in the formation and progression of hamster gliomas; (2) Characterize the biochemical properties of pRb2/p130 associated with its interaction with JCV during cell growth and transformation, and the biochemical effects of this interaction on cyclins and cyclin-dependent kinases (cdks); and (3) structurally and functionally characterize the JCV T-antigen interaction with pRb2/p130 in an in vivo system.
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