Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1980 Jun;77(6):3450–3454. doi: 10.1073/pnas.77.6.3450

Toward a model for the molecular genetics of carcinogenesis in rats.

P C Kimball, M C Simon, N K Mishra
PMCID: PMC349634  PMID: 6251460

Abstract

Cultured rat embryo cells are resistant to neoplastic transformation by chemical carcinogens unless they are extensively subcultured or infected with a murine leukemia virus (MuLV) first. We found that, in normal cultured cells, MuLV activates expression of rat genes that are the progenitors of sarcoma virus genes, but not those of endogenous "leukemia" virus. Elevated levels of sarcoma virus-related RNA in normal cells infected with MuLV were indistinguishable from the levels in cells transformed spontaneously or by a carcinogen or a sarcoma virus. Because of previous reports that some carcinomas in rats also contain elevated levels of sarcoma virus-related RNA, we believe these events can be explained by a molecular genetic model which may be generally valid for initiation of carcinogenesis. The basic elements of the model are: transcriptional activation of all the multiple copies of normal rat progenitors of sarcoma virus genes is required before cellular transformation can be initiated, and initiation occurs when a spontaneous or induced mutation in any one active copy of these same genes generates a dominant transforming function.

Full text

PDF
3450

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson G. R., Robbins K. C. Rat sequences of the Kirsten and Harvey murine sarcoma virus genomes: nature, origin, and expression in rat tumor RNA. J Virol. 1976 Feb;17(2):335–351. doi: 10.1128/jvi.17.2.335-351.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Birnstiel M. L., Sells B. H., Purdom I. F. Kinetic complexity of RNA molecules. J Mol Biol. 1972 Jan 14;63(1):21–39. doi: 10.1016/0022-2836(72)90519-0. [DOI] [PubMed] [Google Scholar]
  3. Britten R. J., Graham D. E., Neufeld B. R. Analysis of repeating DNA sequences by reassociation. Methods Enzymol. 1974;29:363–418. doi: 10.1016/0076-6879(74)29033-5. [DOI] [PubMed] [Google Scholar]
  4. Callahan R., Benveniste R. E., Lieber M. M., Todaro G. J. Nucleic acid homology of murine type-C viral genes. J Virol. 1974 Dec;14(6):1394–1403. doi: 10.1128/jvi.14.6.1394-1403.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Deeley R. G., Gordon J. I., Burns A. T., Mullinix K. P., Binastein M., Goldberg R. F. Primary activation of the vitellogenin gene in the rooster. J Biol Chem. 1977 Nov 25;252(22):8310–8319. [PubMed] [Google Scholar]
  6. Freeman A. E., Igel H. J., Price P. J. I. In vitrol transformation of rat embryo cells: correlations with the known tumorigenic activities of chemicals in rodents. In Vitro. 1975 Mar-Apr;11(2):107–116. doi: 10.1007/BF02624083. [DOI] [PubMed] [Google Scholar]
  7. Freeman A. E., Price P. J., Igel H. J., Young J. C., Maryak J. M., Huebner R. J. Morphological transformation of rat embryo cells induced by diethylnitrosamine and murine leukemia viruses. J Natl Cancer Inst. 1970 Jan;44(1):65–78. [PubMed] [Google Scholar]
  8. Freeman A. E., Weisburger E. K., Weisburger J. H., Wolford R. G., Maryak J. M., Huebner R. J. Transformation of cell cultures as an indication of the carcinogenic potential of chemicals. J Natl Cancer Inst. 1973 Sep;51(3):799–808. doi: 10.1093/jnci/51.3.799. [DOI] [PubMed] [Google Scholar]
  9. HARVEY J. J. AN UNIDENTIFIED VIRUS WHICH CAUSES THE RAPID PRODUCTION OF TUMOURS IN MICE. Nature. 1964 Dec 12;204:1104–1105. doi: 10.1038/2041104b0. [DOI] [PubMed] [Google Scholar]
  10. Herman R. C., Williams J. G., Penman S. Message and non-message sequences adjacent to poly(A) in steady state heterogeneous nuclear RNA of HeLa cells. Cell. 1976 Mar;7(3):429–437. doi: 10.1016/0092-8674(76)90173-2. [DOI] [PubMed] [Google Scholar]
  11. Huebner R. J., Todaro G. J. Oncogenes of RNA tumor viruses as determinants of cancer. Proc Natl Acad Sci U S A. 1969 Nov;64(3):1087–1094. doi: 10.1073/pnas.64.3.1087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Huu Duc-Nguyen, Rosenblum E. N., Zeigel R. F. Persistent infection of a rat kidney cell line with Rauscher murine leukemia virus. J Bacteriol. 1966 Oct;92(4):1133–1140. doi: 10.1128/jb.92.4.1133-1140.1966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kimball P. C., Duesberg P. H. Virus interference by cellular double-stranded ribonucleic acid. J Virol. 1971 Jun;7(6):697–706. doi: 10.1128/jvi.7.6.697-706.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kimball P. C., Michalides R., Colcher D., Schlom J. Characterization of mouse mammary tumor viruses from primary tumor cell cultures. II. Biochemical and biophysical studies. J Natl Cancer Inst. 1976 Jan;56(1):119–124. doi: 10.1093/jnci/56.1.119. [DOI] [PubMed] [Google Scholar]
  15. Maisel J., Klement V., Lai M. M., Ostertag W., Duesberg P. Ribonucleic acid components of murine sarcoma and leukemia viruses. Proc Natl Acad Sci U S A. 1973 Dec;70(12):3536–3540. doi: 10.1073/pnas.70.12.3536. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Mishra N. K., Pant K. J., Wilson D. M., Thomas F. O. Carcinogen-induced mutations at two separate genetic loci are not enhanced by leukaemia virus infection. Nature. 1977 Apr 7;266(5602):548–550. doi: 10.1038/266548a0. [DOI] [PubMed] [Google Scholar]
  17. Mishra N. K., Ryan W. L. Effect of 3-methylcholanthrene and dimethylnitrosamine on anchorage dependence of rat fibroblasts chronically infected with Rauscher leukemia virus. Int J Cancer. 1973 Jan 15;11(1):123–130. doi: 10.1002/ijc.2910110114. [DOI] [PubMed] [Google Scholar]
  18. Scolnick E. M., Howk R. S., Anisowicz A., Peebles P. T., Scher C. D., Parks W. P. Separation of sarcoma virus-specific and leukemia virus-specific genetic sequences of Moloney sarcoma virus. Proc Natl Acad Sci U S A. 1975 Nov;72(11):4650–4654. doi: 10.1073/pnas.72.11.4650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Scolnick E. M., Stephenson J. R., Aaronson S. A. Isolation of temperature-sensitive mutants of murine sarcoma virus. J Virol. 1972 Oct;10(4):653–657. doi: 10.1128/jvi.10.4.653-657.1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Scolnick E. M., Vass W. C., Howk R. S., Duesberg P. H. Defective retrovirus-like 30S RNA species of rat and mouse cells are infectious if packaged by type C helper virus. J Virol. 1979 Mar;29(3):964–972. doi: 10.1128/jvi.29.3.964-972.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Scolnick E. M., Williams D., Maryak J., Vass W., Goldberg R. J., Parks W. P. Type C particle-positive and type C particle-negative rat cell lines: characterization of the coding capacity of endogenous sarcoma virus-specific RNA. J Virol. 1976 Dec;20(3):570–582. doi: 10.1128/jvi.20.3.570-582.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Shih T. Y., Williams D. R., Weeks M. O., Maryak J. M., Vass W. C., Scolnick E. M. Comparison of the genomic organization of Kirsten and Harvey sarcoma viruses. J Virol. 1978 Jul;27(1):45–55. doi: 10.1128/jvi.27.1.45-55.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Shih T. Y., Young H. A., Coffin J. M., Scolnick E. M. Physical map of the Kirsten sarcoma virus genome as determined by fingerprinting RNase T1-resistant oligonucleotides. J Virol. 1978 Jan;25(1):238–252. doi: 10.1128/jvi.25.1.238-252.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Smith R. G., Donehower L., Gallo R. C., Gillespie D. H. Rapid purification of 70S RNA from media of cells producing RNA tumor viruses. J Virol. 1975 Jan;17(1):287–290. doi: 10.1128/jvi.17.1.287-290.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Taylor J. M., Illmensee R., Summers J. Efficeint transcription of RNA into DNA by avian sarcoma virus polymerase. Biochim Biophys Acta. 1976 Sep 6;442(3):324–330. doi: 10.1016/0005-2787(76)90307-5. [DOI] [PubMed] [Google Scholar]
  26. Waters R., Mishra N., Bouck N., DiMayorca G., Regan J. D. Partial inhibition of postreplication repair and enhanced frequency of chemical transformation in rat cells infected with leukemia virus. Proc Natl Acad Sci U S A. 1977 Jan;74(1):238–242. doi: 10.1073/pnas.74.1.238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Young H. A., Wenk M. L., Goodman D. G., Scolnick E. M. Expression of RNA of an endogenous replication-defective retrovirus in rat mammary adenocarcinomas induced by 7,12-dimethylbenz[a]anthracene. J Natl Cancer Inst. 1978 Nov;61(5):1329–1337. doi: 10.1093/jnci/61.5.1329. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES