Sequence comparison in the crossover region of an oncogenic avian retrovirus recombinant and its nononcogenic parent: genetic regions that control growth rate and oncogenic potential.

Abstract

NTRE 7 is an avian retrovirus recombinant of the endogenous nononcogenic Rous-associated virus-0 (RAV-0) and the oncogenic, exogenous, transformationdefective (td) Prague strain of Rous sarcoma virus B (td-PrRSV-B). Oligonucleotide mapping had shown that the recombinant virus is indistinguishable from its RAV-0 parent except for the 3'-end sequences, which were derived from tdPrRSV-B. However, the virus exhibits properties which are typical of an exogenous virus: it grows to high titers in tissue culture, and it is oncogenic in vivo. To accurately define the genetic region responsible for these properties, we determined the nucleotide sequences of the recombinant and its RAV-0 parent by using molecular clones of their DNA. These were compared with sequences already available for PrRSV-C, a virus closely related to the exogenous parent tdPrRSV-B. The results suggested that the crossover event which generated NTRE 7 took place in a region -501 to -401 nucleotides from the 3' end of the td-PrRSV parental genome and that sequences to the right of the recombination region were responsible for its growth properties and oncogenic potential. These sequences included a 148-base-pair exogenous-virus-specific region that was absent from the RAV-0 genome and the U3 region of the long terminal repeat. Since the exogenous-virus-specific sequences are expected to be missing from transformation-defective mutants of the Schmidt-Ruppin strain of RSV, which, like other exogenous viruses, grow to high titers in tissue culture and are oncogenic in vivo, we concluded that the growth properties and oncogenic potential of the exogenous viruses are determined by sequences in the U3 region of the long terminal repeat. However, we propose that the exogenous-virus-specific region may play a role in determining the oncogenic spectrum of a given oncogenic virus.

Jaagsiekte Sheep Retrovirus and Enzootic Nasal Tumor Virus Promoters Drive Gene Expression in All Airway Epithelial Cells of Mice but Only Induce Tumors in the Alveolar Region of the Lungs

“…Early studies with RSV found that viral sequences immediately preceding the 3Ј LTR of the Prague (PrRSV) and Schmidt-Ruppin strains of RSV (SR RSV) enhanced reporter gene expression (18,20). Interestingly, the enhancer domain in PrRSV, termed the exogenous virus-specific region (XSR) (18), was shown to be responsible for differences in oncogenicity (36), and the same region of the avian leukosis virus, subgroup J (ALV-J), termed E, has been shown to contribute to oncogenicity in certain genetic lines of chickens, potentially through an enhancing mechanism (3).…”

Enhancer activity correlates with the oncogenic potential of avian retroviruses.

“…In fact, RAV-0 becomes oncogenic when its own U3 region is replaced by that of RSV (Robinson et al, 1982;Tsichlis et al, 1982). Furthermore, it has been demonstrated that the LTR of a tumorigenic retrovirus (RAV-2) gives rise to a 10-fold higher level of env gene transcription than the RAV-0 LTR (Cullen et al, 1983).…”

“…Since RAV-0 is an endogenous virus which also has the ability to multiply in avian cells, it might be that the loss of enhancer activity evolved to reduce oncogenicity without losing viability. Robinson et al (1982) and Tsichlis et al (1982) have demonstrated that replacing the U3 region of the RAV-0 LTR with the homologous region of td-RSV restores oncogenicity in vivo. Thus, the U3 region determines the potential of a virus to induce malignant diseases such as lymphomas, carcinomas, chondrosarcomas, fibrosarcomas and osteopetrosis Robinson et al, 1982).…”

“…A crucial event in this process is the integration of viral DNA near a cellular proto-oncogene (e.g., c-myc) and apparent de-regulation of its expession (Fung et al, 1981;Hayward et al, 1981;Neel et al, 1981;Payne et al, 1981Payne et al, , 1982Cullen et al, 1984). There are, on the other hand, nononcogenic viruses like RAV-0 (Critten et al, 1979; Hughes, 1982;Tsichlis et al, 1982;Coffin et al, 1983). The endogenous RAV-0 virus can be rescued from the chicken genome so that it can multiply and infect other avian cells.…”

Genetic mapping of a cellular DNA region involved in induction of thymic lymphomas (Mlvi-1) to mouse chromosome 15.

“…Alternatively, oncogene activation and neoplastic disease can also follow the chromosomal integration of a nonacute transforming retrovirus near these potentially transforming host genes. The major retroviral sequences necessary for transformation in avian leukosis virus have been localized to the U3 region of retroviral long terminal repeats (LTRs) (21,22,(31)(32)(33). Recent studies with murine nontransforming retroviruses also argue for the importance of the proviral LTR sequences in determining oncogenicity (3,6,15).…”