Viral Oncogenes and Cellular Prototypes
The structural hallmark of retroviral transforming onc genes is a specific RNA sequence that is unrelated to the essential retroviral genes but closely related to certain cellular prototypes termed proto-onc genes. Two types of onc genes have been distinguished. Type I are onc genes which utilize elements of specific sequences only to encode a transforming protein. Type II onc genes are hybrids which utilize essential viral (typically gag) and specific RNA sequences to encode transforming proteins. Comparisons between viral onc genes and cellular proto-onc genes are reviewed in the light of two competing models for proto-onc function: the quantitative model, which holds that viral onc genes and cellular proto-onc genes are functionally the same and that transformation is the result of enhanced dosage of a cellular proto-onc gene; and the qualitative model, which holds that they are different. Structural comparisons between viral onc genes and cellular prototypes have demonstrated extensive sequence homologies in the primary structures of the specific sequences. However, qualitative differences exist in the structure and organization of viral onc genes and cellular prototypes. These include differences in promoters, minor differences in the primary structure of shared sequences, and absolute differences such as in the presence of sequences which are unique to viral onc genes or to corresponding cellular genetic units. For example, type II hybrid onc genes of retroviruses share only their specific but not their gag-related elements with the cell, and cellular proto-onc genes are interrupted by sequences of nonhomology relative to viral onc genes. In addition, proto-onc gene units may include unique cellular coding sequences not shared with viral onc genes. There is circumstantial evidence that some proto-onc genes are potentially oncogenic after activation (quantitative model) or modification (qualitative model). Activated by an adjacently integrated retroviral promotor, the cellular prototype of the onc gene of the avian acute leukemia virus MC29 was proposed to cause lymphoma and activated by ligation with viral promoter sequences two proto-onc DNAs, those of Moloney and Harvey sarcoma viruses, were found to transform mouse 3T3 cell lines. Mutations presumably conferred 3T3 cell-transforming ability to the proto-onc gene of Harvey sarcoma virus that has been isolated from a human bladder carcinoma cell line. In no case has an unaltered proto-onc as yet been shown to be necessary and sufficient for carcinogenesis. Despite this and structural differences between viral onc genes and cellular proto-onc genes, we cannot at present conclusively distinguish between the quantitative and the qualitative models because a genetic and functional definition of most viral onc genes and of all cellular prototypes of viral onc genes are not as yet available.
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