The recently identified piscine retroviruses and their associate neoplasia will provide new model systems for the investigation of molecular mechanisms of oncogenesis. Walleye dermal sarcoma virus (WDSV) is associated with tumors that develop and regress on a seasonal basis. Therefore, WDSV offers the unique opportunity to study the mechanisms of tumor regression. WDSV is the first example of an acutely transforming, complex retrovirus, which encodes an accessory protein retroviral cyclin (rv-cyclin) with homology to cellular D-type cyclins. Cyclin D1 is an oncogene that is amplified and over-expressed in several humor tumors. The long term objectives of this research are to characterize cellular proteins with unknown function that directly interact with the rv-cyclin and to identify compounds that alter these interactions. We will first determine the subcellular localization of the interacting cellular proteins. Further characterization of these proteins will be done by quantitating the levels of proteins and their transcripts in different cell types and tissues and during development. A fluorescence assay and a counter selection yeast two-hybrid system will be used to screen for compounds that interfere with the binding of rv-cyclin and its interacting cellular proteins. In vitro kinase assays will be used to identify compounds that affect the function of the rv-cyclin/CDK complex. Finally, compounds found to alter the interaction of cellular proteins with WDSV rv-cyclin will be evaluated for their inhibitory effect on immortalization and transformation of primary cells.
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