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. 1984 Jun;50(3):847–853. doi: 10.1128/jvi.50.3.847-853.1984

Oncogenicity by adenovirus is not determined by the transforming region only.

R Bernards, M G de Leeuw, M J Vaessen, A Houweling, A J van der Eb
PMCID: PMC255745  PMID: 6328015

Abstract

We have constructed a nondefective recombinant virus between the nononcogenic adenovirus 5 (Ad5) and the highly oncogenic Ad12. The recombinant genome consists essentially of Ad5 sequences, with the exception of the transforming early region 1 (E1) which is derived from Ad12. HeLa cells infected with the recombinant virus were shown to contain the Ad12-specific E1 proteins of 41 kilodaltons (E1a) and 19 and 54 kilodaltons (both encoded by E1b). The recombinant virus replicated efficiently in human embryonic kidney cells and HeLa cells, showing that the transforming regions of Ad5 and Ad12 had similar functions in productive infection. After the recombinant virus was injected into newborn hamsters, no tumors were produced during an observation period of 200 days. Thus, despite the fact that all products required for oncogenic transformation in vitro were derived from the highly oncogenic Ad12, the recombinant virus did not produce tumors in vivo. These data show that tumor induction by adenovirus virions is not determined only by the gene products of the transforming region.

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Selected References

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  1. Bernards R., Houweling A., Schrier P. I., Bos J. L., Van der Eb A. J. Characterization of cells transformed by Ad5/Ad12 hybrid early region I plasmids. Virology. 1982 Jul 30;120(2):422–432. doi: 10.1016/0042-6822(82)90042-3. [DOI] [PubMed] [Google Scholar]
  2. Bernards R., Schrier P. I., Bos J. L., Van der Eb A. J. Role of adenovirus types 5 and 12 early region 1b tumor antigens in oncogenic transformation. Virology. 1983 May;127(1):45–53. doi: 10.1016/0042-6822(83)90369-0. [DOI] [PubMed] [Google Scholar]
  3. Bernards R., Schrier P. I., Houweling A., Bos J. L., van der Eb A. J., Zijlstra M., Melief C. J. Tumorigenicity of cells transformed by adenovirus type 12 by evasion of T-cell immunity. 1983 Oct 27-Nov 2Nature. 305(5937):776–779. doi: 10.1038/305776a0. [DOI] [PubMed] [Google Scholar]
  4. Bernards R., Vaessen M. J., Van der Eb A. J., Sussenbach J. S. Construction and characterization of an adenovirus type 5/adenovirus type 12 recombinant virus. Virology. 1983 Nov;131(1):30–38. doi: 10.1016/0042-6822(83)90530-5. [DOI] [PubMed] [Google Scholar]
  5. Bos J. L., Jochemsen A. G., Bernards R., Schrier P. I., van Ormondt H., van der Eb A. J. Deletion mutants of region E1a of AD12 E1 plasmids: effect on oncogenic transformation. Virology. 1983 Sep;129(2):393–400. doi: 10.1016/0042-6822(83)90178-2. [DOI] [PubMed] [Google Scholar]
  6. Bos J. L., Polder L. J., Bernards R., Schrier P. I., van den Elsen P. J., van der Eb A. J., van Ormondt H. The 2.2 kb E1b mRNA of human Ad12 and Ad5 codes for two tumor antigens starting at different AUG triplets. Cell. 1981 Nov;27(1 Pt 2):121–131. doi: 10.1016/0092-8674(81)90366-4. [DOI] [PubMed] [Google Scholar]
  7. Brusca J. S., Chinnadurai G. Transforming genes among three different oncogenic subgroups of human adenoviruses have similar replicative functions. J Virol. 1981 Jul;39(1):300–305. doi: 10.1128/jvi.39.1.300-305.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Byrd P., Brown K. W., Gallimore P. H. Malignant transformation of human embryo retinoblasts by cloned adenovirus 12 DNA. Nature. 1982 Jul 1;298(5869):69–71. doi: 10.1038/298069a0. [DOI] [PubMed] [Google Scholar]
  9. Doerfler W. Nonproductive infection of baby hamster kidney cells (BHK21) with adenovirus type 12. Virology. 1969 Aug;38(4):587–606. doi: 10.1016/0042-6822(69)90179-2. [DOI] [PubMed] [Google Scholar]
  10. Downey J. F., Rowe D. T., Bacchetti S., Graham F. L., Bayley S. T. Mapping of a 14,000-dalton antigen to early region 4 of the human adenovirus 5 genome. J Virol. 1983 Feb;45(2):514–523. doi: 10.1128/jvi.45.2.514-523.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Freeman A. E., Black P. H., Wolford R., Huebner R. J. Adenovirus type 12-rat embryo transformation system. J Virol. 1967 Apr;1(2):362–367. doi: 10.1128/jvi.1.2.362-367.1967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gallimore P. H., McDougall J. K., Chen L. B. In vitro traits of adenovirus-transformed cell lines and their relevance to tumorigenicity in nude mice. Cell. 1977 Apr;10(4):669–678. doi: 10.1016/0092-8674(77)90100-3. [DOI] [PubMed] [Google Scholar]
  13. Gallimore P. H., Paraskeva C. A study to determine the reasons for differences in the tumorigenicity of rat cell lines transformed by adenovirus 2 and adenovirus 12. Cold Spring Harb Symp Quant Biol. 1980;44(Pt 1):703–713. doi: 10.1101/sqb.1980.044.01.075. [DOI] [PubMed] [Google Scholar]
  14. Galos R. S., Williams J., Shenk T., Jones N. Physical location of host-range mutations of adenovirus type 5; deletion and marker-rescue mapping. Virology. 1980 Jul 30;104(2):510–513. doi: 10.1016/0042-6822(80)90356-6. [DOI] [PubMed] [Google Scholar]
  15. Graham F. L., Harrison T., Williams J. Defective transforming capacity of adenovirus type 5 host-range mutants. Virology. 1978 May 1;86(1):10–21. doi: 10.1016/0042-6822(78)90003-x. [DOI] [PubMed] [Google Scholar]
  16. Graham F. L., Smiley J., Russell W. C., Nairn R. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol. 1977 Jul;36(1):59–74. doi: 10.1099/0022-1317-36-1-59. [DOI] [PubMed] [Google Scholar]
  17. Harrison T., Graham F., Williams J. Host-range mutants of adenovirus type 5 defective for growth in HeLa cells. Virology. 1977 Mar;77(1):319–329. doi: 10.1016/0042-6822(77)90428-7. [DOI] [PubMed] [Google Scholar]
  18. Harwood L. M., Gallimore P. H. A study of the oncogenicity of adenovirus type 2 transformed rat embryo cells. Int J Cancer. 1975 Sep 15;16(3):498–508. doi: 10.1002/ijc.2910160317. [DOI] [PubMed] [Google Scholar]
  19. Ho Y. S., Galos R., Williams J. Isolation of type 5 adenovirus mutants with a cold-sensitive host range phenotype: genetic evidence of an adenovirus transformation maintenance function. Virology. 1982 Oct 15;122(1):109–124. doi: 10.1016/0042-6822(82)90381-6. [DOI] [PubMed] [Google Scholar]
  20. Houweling A., van den Elsen P. J., van der Eb A. J. Partial transformation of primary rat cells by the leftmost 4.5% fragment of adenovirus 5 DNA. Virology. 1980 Sep;105(2):537–550. doi: 10.1016/0042-6822(80)90054-9. [DOI] [PubMed] [Google Scholar]
  21. Jochemsen H., Daniels G. S., Lupker J. H., van der Eb A. J. Identification and mapping of the early gene products of adenovirus type 12. Virology. 1980 Sep;105(2):551–563. doi: 10.1016/0042-6822(80)90055-0. [DOI] [PubMed] [Google Scholar]
  22. Jochemsen H., Daniëls G. S., Hertoghs J. J., Schrier P. I., van den Elsen P. J., van der EB A. J. Identification of adenovirus-type 12 gene products involved in transformation and oncogenesis. Virology. 1982 Oct 15;122(1):15–28. doi: 10.1016/0042-6822(82)90373-7. [DOI] [PubMed] [Google Scholar]
  23. Jones N., Shenk T. Isolation of adenovirus type 5 host range deletion mutants defective for transformation of rat embryo cells. Cell. 1979 Jul;17(3):683–689. doi: 10.1016/0092-8674(79)90275-7. [DOI] [PubMed] [Google Scholar]
  24. Lewis A. M., Jr, Cook J. L. Spectrum of tumorigenic phenotypes among adenovirus 2-, adenovirus 12-, and simian virus 40-transformed Syrian hamster cells defined by host cellular immune-tumor cell interactions. Cancer Res. 1982 Mar;42(3):939–944. [PubMed] [Google Scholar]
  25. Mak S., Mak I., Smiley J. R., Graham F. L. Tumorigenicity and viral gene expression in rat cells transformed by Ad 12 virions or by the EcoRI c fragment of Ad 12 DNA. Virology. 1979 Oct 30;98(2):456–460. doi: 10.1016/0042-6822(79)90568-3. [DOI] [PubMed] [Google Scholar]
  26. McAllister R. M., Nicolson M. O., Lewis A. M., Jr, Macpherson I., Huebner R. J. Transformation of rat embryo cells by adenovirus type 1. J Gen Virol. 1969 Jan;4(1):29–36. doi: 10.1099/0022-1317-4-1-29. [DOI] [PubMed] [Google Scholar]
  27. Minekawa Y., Ishibashi M., Yasue H., Takahashi M. Characterization of host-range and temperature-sensitive mutants of adenovirus type 5 with particular regard to transformation of a hamster embryo cell line (Nil). Virology. 1976 May;71(1):97–110. doi: 10.1016/0042-6822(76)90097-0. [DOI] [PubMed] [Google Scholar]
  28. Rowe D. T., Graham F. L. Complementation of adenovirus type 5 host range mutants by adenovirus type 12 in coinfected HeLa and BHK-21 cells. J Virol. 1981 Apr;38(1):191–197. doi: 10.1128/jvi.38.1.191-197.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ruben M., Bacchetti S., Graham F. L. Integration and expression of viral DNA in cells transformed by host range mutants of adenovirus type 5. J Virol. 1982 Feb;41(2):674–685. doi: 10.1128/jvi.41.2.674-685.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schrier P. I., Bernards R., Vaessen R. T., Houweling A., van der Eb A. J. Expression of class I major histocompatibility antigens switched off by highly oncogenic adenovirus 12 in transformed rat cells. 1983 Oct 27-Nov 2Nature. 305(5937):771–775. doi: 10.1038/305771a0. [DOI] [PubMed] [Google Scholar]
  31. Shiroki K., Handa H., Shimojo H., Yano S., Ojima S., Fujinaga K. Establishment and characterization of rat cell lines transformed by restriction endonuclease fragments of adenovirus 12 DNA. Virology. 1977 Oct 15;82(2):462–471. doi: 10.1016/0042-6822(77)90019-8. [DOI] [PubMed] [Google Scholar]
  32. Signäs C., Katze M. G., Persson H., Philipson L. An adenovirus glycoprotein binds heavy chains of class I transplantation antigens from man and mouse. Nature. 1982 Sep 9;299(5879):175–178. doi: 10.1038/299175a0. [DOI] [PubMed] [Google Scholar]
  33. Stow N. D. The infectivity of adenovirus genomes lacking DNA sequences from their left-hand termini. Nucleic Acids Res. 1982 Sep 11;10(17):5105–5119. doi: 10.1093/nar/10.17.5105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Takahashi M., Minekawa Y., Yamanishi K. Transformation of a hamster embryo cell line (Nil) with a host-dependent mutant of adenovirus type 5. Virology. 1974 Jan;57(1):300–303. doi: 10.1016/0042-6822(74)90133-0. [DOI] [PubMed] [Google Scholar]
  35. Takahashi M., Ogino T., Baba K., Onaka M. Synthesis of deoxyribonucleic acid in human and hamster kidney cells infected with human adenovirus types 5 and 12. Virology. 1969 Apr;37(4):513–520. doi: 10.1016/0042-6822(69)90269-4. [DOI] [PubMed] [Google Scholar]
  36. Williams J. F. Oncogenic transformation of hamster embryo cells in vitro by adenovirus type 5. Nature. 1973 May 18;243(5403):162–163. doi: 10.1038/243162a0. [DOI] [PubMed] [Google Scholar]
  37. Williams J., Ho Y. S., Galos R. Evidence for functional relatedness of products encoded by the transforming sequences of human adenovirus types 5 and 12. Virology. 1981 Apr 15;110(1):208–212. doi: 10.1016/0042-6822(81)90023-4. [DOI] [PubMed] [Google Scholar]
  38. Wilson M. C., Darnell J. E., Jr Control of messenger RNA concentration by differential cytoplasmic half-life. Adenovirus messenger RNAs from transcription units 1A and 1B. J Mol Biol. 1981 May 25;148(3):231–251. doi: 10.1016/0022-2836(81)90537-4. [DOI] [PubMed] [Google Scholar]
  39. van der Eb A. J., Graham F. L. Assay of transforming activity of tumor virus DNA. Methods Enzymol. 1980;65(1):826–839. doi: 10.1016/s0076-6879(80)65077-0. [DOI] [PubMed] [Google Scholar]

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