The integration of human DNA and expression tumor virus genes : (cell transformation, transcription, integration, human cancer)
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DNA tumor viruses offer excellent model systems to study the molecular biology of eucaryotic cells and to establish the molecular basis for cell transformation. Our laboratory has focused on the human adenovirus type 2 (Ad2), which replicates in human cells, and transforms rodent cells. We have studied the physical interaction of the Ad2-transforming genes with the transformed cell, and have studied the expression of these genes at the RNA and protein level both in transformed and in infected cells. Finally, we have investigated whether human cancers contain the transforming genes of 4 of the 5 groups of human adenoviruses, as well as the transforming genes of other DNA tumor viruses including human papovaviruses, papillomaviruses, and herpes viruses. We have found that Ad2-transformed cells contain the left portion of the viral genome, i.e. early gene region El, present in an integrated state and with the El genes intact, i.e. collinear with the viral genome. These transforming genes are expressed as the same mRNA and polypeptide molecules that are expressed in productively infected human cells. This suggests that integration and expression of adenovirus-transforming genes are necessary for adenovirus-induced cell transformation. The transforming genes, as well as other Ad2 early genes not involved in transformation, consist of overlapping sets of genes that encode overlapping mRNAs and polypeptides; the overlapping mRNAs appear to be generated via post-transcriptional splicing mechanisms. By immunoprecipitation with antisera to Ad2- transformed cells, two-dimensional gel electrophoresis, cell-free translation, and peptide mapping, we have identified two (53K/47K/41K/35K family, 53K/19K/17K-23K family) or possibly more families of polypeptides with overlapping amino acid sequences that are coded by the transforming region. Little is known about the functions of the Ad2-transforming proteins. In studies on the presence of DNA-tumor-virus-transforming genes sequences in human cancers, we did not detect sequences of four of the five groups of human Ads, human BK virus, and two of the five types of human papillomaviruses in human cancers representing about 50 percent of the cancer incidence in the United States. These molecular-hybridization analyses were done at a sensitivity that could detect one copy per cell of 1 percent-3 percent of the viral genome (Ad) or less (papovaviruses). Thus, these results are strong evidence that none of the cancers assayed were induced by any of the DNA tumor viruses studied. However, we have only touched the tip of the iceberg and much further work is necessary to understand fully whether DNA tumor viruses may be involved in the etiology of human cancer.