Walleye dermal sarcoma (WDS) is a common disease of walleye fish in the United States and Canada. These proliferative lesions are present autumn through winter and regress in the spring. Walleye dermal sarcoma virus (WDSV), a retrovirus distantly related to other members of the family Retroviridae, has been etiologically linked to the development of WDS. We have reported that the D-cyclin homologue [retroviral (rv) cyclin] encoded by WDSV rescues yeast conditionally deficient for cyclin synthesis from growth arrest and that WDSV-cyclin mRNA is present in developing tumors. These data strongly suggest that the rv-cyclin plays a central role in the development of WDS. To test the ability of the WDSV rv-cyclin to induce cell proliferation, we have generated transgenic mice expressing the rv-cyclin in squamous epithelia from the bovine keratin-5 promoter. The transgenic animals were smaller than littermates, had reduced numbers of hair follicles, and transgenic females did not lactate properly. Following injury the transgenic animals developed severe squamous epithelial hyperplasia and dysplasia with ultrastructural characteristics of neoplastic squamous epithelium. Immunocytochemistry studies demonstrated that the hyperplastic epithelium stained positive for cytokeratin and were abnormally differentiated. Furthermore, the rv-cyclin protein was detected in the thickened basal cell layers of the proliferating lesions. These data are the first to indicate that the highly divergent WDSV rv-cyclin is a very potent stimulator of eukaryotic cell proliferation and to demonstrate the potential of a cyclin homologue encoded by a retrovirus to induce hyperplastic skin lesions. Knowledge concerning mechanisms of cell cycle control and cancer has been greatly enhanced through the study of oncogenic animal viruses. Walleye dermal sarcoma (WDS) is a cutaneous tumor that was first reported on feral walleye fish (Stizostedion vitreum) from Oneida Lake in New York by Walker (1) who later reported the presence of type C retroviral particles, walleye dermal sarcoma virus (WDSV) in lesions (2). The sarcoma is neither a rare nor a geographically limited disease, as up to 27% of the walleye population of Oneida Lake have tumors in some years and the disease has been reported on walleyes throughout the higher latitudes of North America (3, 4). One of the remarkable characteristics of WDS is its seasonal induction and regression. Tumors are observed from late fall through early spring when they regress; lesions are absent in the summer months. The molecular events leading to the seasonal induction and regression of WDS are not known but likely include complex interactions of host factors, e.g., hormonally regulated changes in viral gene expression and variations in the immune response of fish at different water temperatures (5). This tenet is supported by (i) the presence of retroviral type C particles in regressing tumors but not in developing tumors; (ii) observations that the gene expression pattern of WDSV changes both quantitatively a...
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