"Hit-and-run" transformation by adenovirus oncogenes.
According to classical concepts of viral oncogenesis, the persistence of virus-specific oncogenes is required to maintain the transformed cellular phenotype. In contrast, the "hit-and-run" hypothesis claims that viruses can mediate cellular transformation through an initial "hit," while maintenance of the transformed state is compatible with the loss ("run") of viral molecules. It is well established that the adenovirus E1A and E1B gene products can cooperatively transform primary human and rodent cells to a tumorigenic phenotype and that these cells permanently express the viral oncogenes. Additionally, recent studies have shown that the adenovirus E4 region encodes two novel oncoproteins, the products of E4orf6 and E4orf3, which cooperate with the viral E1A proteins to transform primary rat cells in an E1B-like fashion. Unexpectedly, however, cells transformed by E1A and either E4orf6 or E4orf3 fail to express the viral E4 gene products, and only a subset contain E1A proteins. In fact, the majority of these cells lack E4- and E1A-specific DNA sequences, indicating that transformation occurred through a hit-and-run mechanism. We provide evidence that the unusual transforming activities of the adenoviral oncoproteins may be due to their mutagenic potential. Our results strongly support the possibility that even tumors that lack any detectable virus-specific molecules can be of viral origin, which could have a significant impact on the use of adenoviral vectors for gene therapy.
Institut für Medizinische Mikrobiologie und Hygiene, Universität Regensburg, D-93053 Regensburg, Germany.
M
M
Nevels
B
B
Täuber
T
T
Spruss
H
H
Wolf
T
T
Dobner
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000235:genetics* / Q000502:physiology; D017504:Adenovirus E4 Proteins / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D004279:DNA, Viral / Q000737:chemistry; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D009154:Mutation; D009857:Oncogenes; D051381:Rats; D017207:Rats, Sprague-Dawley
D017500:Adenovirus E1A Proteins; D017504:Adenovirus E4 Proteins; D004279:DNA, Viral; D007041:Hypoxanthine Phosphoribosyltransferase