JC virus is a common neurotropic polyoma virus. The oncogenicity of this virus has been amply demonstrated in hamsters and non-human primates and also in transgenic mice expressing JV virus large T-antigen. However, unlike the closely related BK virus and simian vacuolating virus, SV40, JCV exhibits a restricted tissue tropism which is reflected in the formation of neural tumors. The tissue-specific malignant transformation of neuroectodermal cells in animals as a result of JC virus infection and/or JCV T-antigen expression provides a unique opportunity to study the development and genesis of glioblastomas in the whole animal. The generation of these tumors is likely due to expression of the viral large T-antigen, due in part to its ability to bind and functionally inactivate the retinoblastoma tumor suppressor protein, pRb. Inactivation of pRb may also be accomplished by phosphorylation of this protein by a series of cyclins and their associated kinases including cyclin D:cdk4,6 and cyclin E:cdk2. Earlier studies have indicated an important role for transforming growth factor, TGFbeta, in inducing activities of these cyclin/cdk complexes, and thus converting pRb to its phosphorylated forms. Association of pRb with T-antigen or its phosphorylation results in liberation of the transcription factor, E2F from the Rb:E2F complex. E2F, in turn, stimulates expression of genes needed for transition through G0/G1 to S phase. Results from our and other laboratories have indicated that E2F and TGFbeta may mutually regulate each others' expression and that may alter the physiological balance required for the control of cell proliferation. Moreover, our recent studies have led to the identification of novel E2F related protein(s), GEAPs, in hamster glial cells which modulate transcription of S-phase specific gene. In this proposal we will focus on the interplay between cytokines (TGFbeta) and the cell cycle regulators, i.e., the E2F family of transcription factors to evaluate their mechanism of action in the pathogenesis of gliomas in a well-controlled in vivo system. The use of integrated MRI and neurohistopathological approaches will allow us to perform our molecular biological studies in highly characterized tumor tissue and cells during tumor development. We will perform parallel studies to evaluate the level of TGFbeta, E2F, and Rb gene expression and their activities during tumor formation, and by de-regulating their expression at various stages of cell cycle and tumor formation evaluate their importance in the cascade of events which leads to the genesis of cancer cells in brain. The results of these experiments, for the first time, will determine whether delicate balance in the expression of TGFbeta and E2F during the cell cycle phases play a role in the uncontrolled proliferation of cells and tumor formation in the experimental animal.
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