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. 1987 Jun;7(6):2196–2200. doi: 10.1128/mcb.7.6.2196

Interferon-induced revertants of ras-transformed cells: resistance to transformation by specific oncogenes and retransformation by 5-azacytidine.

D Samid, D M Flessate, R M Friedman
PMCID: PMC365343  PMID: 2439904

Abstract

Prolonged alpha/beta interferon (IFN-alpha/beta) treatment of NIH 3T3 cells transformed by a long terminal repeat-activated Ha-ras proto-oncogene resulted in revertants that maintained a nontransformed phenotype long after IFN treatment had been discontinued. Cloned persistent revertants (PRs) produced large amounts of the ras-encoded p21 and were refractile to transformation by EJras DNA and by transforming retroviruses which carried the v-Ha-ras, v-Ki-ras, v-abl, or v-fes oncogene. Transient treatment either in vitro or in vivo with cytidine analogs that alter gene expression by inhibiting DNA methylation resulted in transformation of PR, but not of NIH 3T3, cells. The PR retransformants reverted again with IFN, suggesting that DNA methylation is involved in IFN-induced persistent reversion.

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Selected References

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

  1. Borden E. C. Interferons and cancer: how the promise is being kept. Interferon. 1983;5:43–83. [PubMed] [Google Scholar]
  2. Bouck N., Kokkinakis D., Ostrowsky J. Induction of a step in carcinogenesis that is normally associated with mutagenesis by nonmutagenic concentrations of 5-azacytidine. Mol Cell Biol. 1984 Jul;4(7):1231–1237. doi: 10.1128/mcb.4.7.1231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brouty-Boyé D., Wybier-Franqui J., Calvo C., Feunteun J., Gresser I. Reversibility of the transformed and neoplastic phenotype. IV. Effects of long-term interferon treatment of C3H/10T1/2 cells transformed by methylcholanthrene and SV40 virus. Int J Cancer. 1984 Jul 15;34(1):107–112. doi: 10.1002/ijc.2910340119. [DOI] [PubMed] [Google Scholar]
  4. Chang E. H., Furth M. E., Scolnick E. M., Lowy D. R. Tumorigenic transformation of mammalian cells induced by a normal human gene homologous to the oncogene of Harvey murine sarcoma virus. Nature. 1982 Jun 10;297(5866):479–483. doi: 10.1038/297479a0. [DOI] [PubMed] [Google Scholar]
  5. Chany C., Vignal M. Effect of prolonged interferon treatment on mouse embryonic fibroblasts transformed by murine sarcoma virus. J Gen Virol. 1970 Jun;7(3):203–210. doi: 10.1099/0022-1317-7-3-203. [DOI] [PubMed] [Google Scholar]
  6. Cooper G. M. Cellular transforming genes. Science. 1982 Aug 27;217(4562):801–806. doi: 10.1126/science.6285471. [DOI] [PubMed] [Google Scholar]
  7. Craig R. W., Sager R. Suppression of tumorigenicity in hybrids of normal and oncogene-transformed CHEF cells. Proc Natl Acad Sci U S A. 1985 Apr;82(7):2062–2066. doi: 10.1073/pnas.82.7.2062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Doerfler W. DNA methylation and gene activity. Annu Rev Biochem. 1983;52:93–124. doi: 10.1146/annurev.bi.52.070183.000521. [DOI] [PubMed] [Google Scholar]
  9. Dotto G. P., Parada L. F., Weinberg R. A. Specific growth response of ras-transformed embryo fibroblasts to tumour promoters. Nature. 1985 Dec 5;318(6045):472–475. doi: 10.1038/318472a0. [DOI] [PubMed] [Google Scholar]
  10. Duran-Troise G., Bassin R. H., Rein A., Gerwin B. I. Loss of Fv-1 restriction in Balb/3T3 cells following infection with a single N tropic murine leukemia virus particle. Cell. 1977 Mar;10(3):479–488. doi: 10.1016/0092-8674(77)90035-6. [DOI] [PubMed] [Google Scholar]
  11. Emanoil-Ravier R., Pochart F., Canivet M., Garcette M., Tobaly-Tapiero J., Peries J. Interferon-mediated regulation of myc and Ki-ras oncogene expression in long-term-treated murine viral transformed cells. J Interferon Res. 1985 Fall;5(4):613–619. doi: 10.1089/jir.1985.5.613. [DOI] [PubMed] [Google Scholar]
  12. Feinberg A. P., Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983 Jan 6;301(5895):89–92. doi: 10.1038/301089a0. [DOI] [PubMed] [Google Scholar]
  13. Franza B. R., Jr, Maruyama K., Garrels J. I., Ruley H. E. In vitro establishment is not a sufficient prerequisite for transformation by activated ras oncogenes. Cell. 1986 Feb 14;44(3):409–418. doi: 10.1016/0092-8674(86)90462-9. [DOI] [PubMed] [Google Scholar]
  14. Friedman R. L., Manly S. P., McMahon M., Kerr I. M., Stark G. R. Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells. Cell. 1984 Oct;38(3):745–755. doi: 10.1016/0092-8674(84)90270-8. [DOI] [PubMed] [Google Scholar]
  15. Furth M. E., Davis L. J., Fleurdelys B., Scolnick E. M. Monoclonal antibodies to the p21 products of the transforming gene of Harvey murine sarcoma virus and of the cellular ras gene family. J Virol. 1982 Jul;43(1):294–304. doi: 10.1128/jvi.43.1.294-304.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gahrton G. Treatment of acute leukemia--advances in chemotherapy, immunotherapy, and bone marrow transplantation. Adv Cancer Res. 1983;40:255–329. doi: 10.1016/s0065-230x(08)60682-x. [DOI] [PubMed] [Google Scholar]
  17. Geiser A. G., Der C. J., Marshall C. J., Stanbridge E. J. Suppression of tumorigenicity with continued expression of the c-Ha-ras oncogene in EJ bladder carcinoma-human fibroblast hybrid cells. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5209–5213. doi: 10.1073/pnas.83.14.5209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  19. Harrison J. J., Anisowicz A., Gadi I. K., Raffeld M., Sager R. Azacytidine-induced tumorigenesis of CHEF/18 cells: correlated DNA methylation and chromosome changes. Proc Natl Acad Sci U S A. 1983 Nov;80(21):6606–6610. doi: 10.1073/pnas.80.21.6606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hicks N. J., Morris A. G., Burke D. C. Partial reversion of the transformed phenotype of murine sarcoma virus-transformed cells in the presence of interferon: a possible mechanism for the anti-tumour effect of interferon. J Cell Sci. 1981 Jun;49:225–236. doi: 10.1242/jcs.49.1.225. [DOI] [PubMed] [Google Scholar]
  21. Hsiao W. L., Gattoni-Celli S., Weinstein I. B. Effects of 5-azacytidine on the progressive nature of cell transformation. Mol Cell Biol. 1985 Jul;5(7):1800–1803. doi: 10.1128/mcb.5.7.1800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jones P. A., Taylor S. M. Cellular differentiation, cytidine analogs and DNA methylation. Cell. 1980 May;20(1):85–93. doi: 10.1016/0092-8674(80)90237-8. [DOI] [PubMed] [Google Scholar]
  23. Lin S. L., Garber E. A., Wang E., Caliguiri L. A., Schellekens H., Goldberg A. R., Tamm I. Reduced synthesis of pp60src and expression of the transformation-related phenotype in interferon-treated Rous sarcoma virus-transformed rat cells. Mol Cell Biol. 1983 Sep;3(9):1656–1664. doi: 10.1128/mcb.3.9.1656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Noda M., Selinger Z., Scolnick E. M., Bassin R. H. Flat revertants isolated from Kirsten sarcoma virus-transformed cells are resistant to the action of specific oncogenes. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5602–5606. doi: 10.1073/pnas.80.18.5602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Norton J. D., Cook F., Roberts P. C., Clewley J. P., Avery R. J. Expression of Kirsten murine sarcoma virus in transformed nonproducer and revertant NIH/3T3 cells: evidence for cell-mediated resistance to a viral oncogene in phenotypic reversion. J Virol. 1984 May;50(2):439–444. doi: 10.1128/jvi.50.2.439-444.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pulciani S., Santos E., Long L. K., Sorrentino V., Barbacid M. ras gene Amplification and malignant transformation. Mol Cell Biol. 1985 Oct;5(10):2836–2841. doi: 10.1128/mcb.5.10.2836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Riggs A. D., Jones P. A. 5-methylcytosine, gene regulation, and cancer. Adv Cancer Res. 1983;40:1–30. doi: 10.1016/s0065-230x(08)60678-8. [DOI] [PubMed] [Google Scholar]
  28. Sager R., Tanaka K., Lau C. C., Ebina Y., Anisowicz A. Resistance of human cells to tumorigenesis induced by cloned transforming genes. Proc Natl Acad Sci U S A. 1983 Dec;80(24):7601–7605. doi: 10.1073/pnas.80.24.7601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Samid D., Chang E. H., Friedman R. M. Biochemical correlates of phenotypic reversion in interferon-treated mouse cells transformed by a human oncogene. Biochem Biophys Res Commun. 1984 Feb 29;119(1):21–28. doi: 10.1016/0006-291x(84)91612-7. [DOI] [PubMed] [Google Scholar]
  30. Samid D., Chang E. H., Friedman R. M. Development of transformed phenotype induced by a human ras oncogene is inhibited by interferon. Biochem Biophys Res Commun. 1985 Jan 16;126(1):509–516. doi: 10.1016/0006-291x(85)90635-7. [DOI] [PubMed] [Google Scholar]
  31. Samid D., Chang E. H., Friedman R. M., Schaff Z., Greene J. J. Biological and morphological characteristics of phenotypic revertants appearing in interferon-treated mouse cells transformed by a human oncogene. J Exp Pathol. 1985 Fall;2(3):211–222. [PubMed] [Google Scholar]
  32. Shih C., Weinberg R. A. Isolation of a transforming sequence from a human bladder carcinoma cell line. Cell. 1982 May;29(1):161–169. doi: 10.1016/0092-8674(82)90100-3. [DOI] [PubMed] [Google Scholar]
  33. Shih T. Y., Weeks M. O. Oncogenes and cancer: the p21 ras genes. Cancer Invest. 1984;2(2):109–123. doi: 10.3109/07357908409020294. [DOI] [PubMed] [Google Scholar]
  34. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  35. Southern P. J., Berg P. Transformation of mammalian cells to antibiotic resistance with a bacterial gene under control of the SV40 early region promoter. J Mol Appl Genet. 1982;1(4):327–341. [PubMed] [Google Scholar]
  36. Tabin C. J., Bradley S. M., Bargmann C. I., Weinberg R. A., Papageorge A. G., Scolnick E. M., Dhar R., Lowy D. R., Chang E. H. Mechanism of activation of a human oncogene. Nature. 1982 Nov 11;300(5888):143–149. doi: 10.1038/300143a0. [DOI] [PubMed] [Google Scholar]
  37. Trainer D. L., Kline T., Mallon F., Greig R., Poste G. Effect of 5-azacytidine on DNA methylation and the malignant properties of B16 melanoma cells. Cancer Res. 1985 Dec;45(12 Pt 1):6124–6130. [PubMed] [Google Scholar]
  38. Weinberg R. A. The action of oncogenes in the cytoplasm and nucleus. Science. 1985 Nov 15;230(4727):770–776. doi: 10.1126/science.2997917. [DOI] [PubMed] [Google Scholar]

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