The transforming potential of the human papillomavirus (HPV) type 16 has been defined largely in the E7, E6, and E5 oncoproteins, with the major transforming capability residing in the E7 gene. In this paper, we found that in cooperation with the activated ras, the HPV16 E7 gene when expressed in a retroviral vector could fully transform baby rat kidney (BRK) cells in transfections, whereas the same construct could only immortalize the BRK cells following retroviral infection. This inability to transform correlated with the low levels of E7 gene RNA expression in the viral infected cells, which harbor a lower number of copies of the E7 gene constructs. Cotransfection of the expression vector FV2E7, which gives high levels of E7 gene expression, and activated ras lead to rapid and efficient morphological transformation of BRK cells which grew easily in soft agar and induced large tumors in athymic nude mice. In contrast, cotransfections of the expression vector FV1E7, which gives lower levels of E7 gene expression, produced much lower numbers of transformed colonies which took longer to form, showed a retarded growth on soft agar, and induced smaller tumors in nude mice. Under these conditions, colonies of immortalized, but morphologically untransformed cells formed in large numbers. These results indicate that the transforming potential is directly correlated to the expression levels of the oncoprotein and that a threshold level of the E7 oncoprotein may be required before the cells can be fully transformed. This supports the hypothesis that the transformation processes include at least two separate and continuous steps which first lead to immortalization and then to metastasis, in agreement with the clinical progression of genital tumors from benign to malignancy. Such a progression may involve enhanced expression of the oncoproteins.
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