We have studied tumorigenic transformation of mouse tissue culture cells by bovine papillomavirus (BPV) as a model of papillomavirus-induced cell proliferation. When BPV or its 7.9-kb full-length viral DNA genome induces focal transformation of mouse calls, the viral DNA is maintained in the transformed cells as multiple extrachromosomal copies. The transforming capacity was initially localized to a 69% subgenomic fragment of the viral DNA genome. We have further characterized the BPV DNA

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... ces that can encode the transform ing function by generating and analyzing the transform ing activity of a series of BPV DNA deletion mutants. The results indicated that two discontinuous segments of the viral DNA are required for transformation. One segment, near the 5' end of the 69% transforming frag ment, probably represents a control element of the viral DNA. The second segment, which lies within the 3' end of the 69% fragment, encodes transforming sequences of the viral DNA. A retroviral control element (the long terminal repeat DNA of Harvey murine sarcoma virus) will activate the 2.3-kb segment at the 3' end of the 69% fragment to transform the mouse cells. Papillomaviruses (PV), which form a subgroup of the papo vaviruses (papova = papilloma, polyoma, and vacuolating vi ruses), induce benign epithelial proliferations (warts, papillo mas) that may undergo malignant conversion in certain settings [1] [2] [3] . Their virions (viral particles) are small (55 nm in diam eter), nonenveloped spheres. The PV genome is an 8000-nu cleotide-Iong (8 kb), circular, double-stranded DNA molecule. PVs are widely distributed among mammalian species, in cluding humans, rabbits, cows, and dogs. However, each virus induces papillomas only in the species that is its natural host. Virus replication (the production of progeny virions) is confined to nuclei of the upper epidermal layers. A few copies of the viral DNA genome are thought to be present in the cells of the lower epidermal layers, including basal cells, but no data di rectly support this conjecture. Progress in studying the biology of PV has been hampered by the lack of a suitable tissue culture system for propagation of these viruses. While complete replication of PV has not yet been achieved in vitro, we have developed an in vitro cell transformation assay for bovine papilloma viruses (BPV) types 1 and 2 [4]. These latter viruses induce fibropapillomas, while infection by most PVs (including all known human PVs) results in papillomas. Even with BPV -induced fibropapillomas, virus replication is confined to the epidermal cells, although viral DNA is found in the dermal fibroblasts. The BPV-mediated transformation of tissue culture cells is probably related to the