Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1991 Nov;65(11):6307–6311. doi: 10.1128/jvi.65.11.6307-6311.1991

Short-term treatment with gamma interferon induces stable reversion of ras-transformed mouse fibroblasts.

B Seliger 1, K Pfizenmaier 1, R Schäfer 1
PMCID: PMC250340  PMID: 1717721

Abstract

Persistent revertants have been generated from NIH 3T3 cells transformed by an activated human Ha-ras gene after short-term gamma interferon treatment in the presence of the cardiac aminoglycoside ouabain. Normal fibroblastlike morphology and anchorage dependence are restored in revertants. Tumorigenicity in nude mice is abolished. The revertants continue to express high steady-state levels of the ras oncogene. Partial retransformation of reverted cells is induced after 5-azacytidine treatment or after infection with retrovirus vectors carrying the v-abl, v-fes, v-myc, or v-src oncogene. The revertants resist the transforming activities of the v-Ha-ras and v-mos oncogenes.

Full text

PDF
6307

Images in this article

Selected References

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

  1. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  2. Cleveland D. W., Lopata M. A., MacDonald R. J., Cowan N. J., Rutter W. J., Kirschner M. W. Number and evolutionary conservation of alpha- and beta-tubulin and cytoplasmic beta- and gamma-actin genes using specific cloned cDNA probes. Cell. 1980 May;20(1):95–105. doi: 10.1016/0092-8674(80)90238-x. [DOI] [PubMed] [Google Scholar]
  3. Contente S., Kenyon K., Rimoldi D., Friedman R. M. Expression of gene rrg is associated with reversion of NIH 3T3 transformed by LTR-c-H-ras. Science. 1990 Aug 17;249(4970):796–798. doi: 10.1126/science.1697103. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Ellis R. W., Defeo D., Shih T. Y., Gonda M. A., Young H. A., Tsuchida N., Lowy D. R., Scolnick E. M. The p21 src genes of Harvey and Kirsten sarcoma viruses originate from divergent members of a family of normal vertebrate genes. Nature. 1981 Aug 6;292(5823):506–511. doi: 10.1038/292506a0. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. 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]
  8. Griegel S., Traub O., Willecke K., Schäfer R. Suppression and re-expression of transformed phenotype in hybrids of HA-ras-1-transformed rat-1 cells and early-passage rat embryonic fibroblasts. Int J Cancer. 1986 Nov 15;38(5):697–705. doi: 10.1002/ijc.2910380513. [DOI] [PubMed] [Google Scholar]
  9. Haynes J. R., Downing J. R. A recessive cellular mutation in v-fes-transformed mink cells restores contact inhibition and anchorage-dependent growth. Mol Cell Biol. 1988 Jun;8(6):2419–2427. doi: 10.1128/mcb.8.6.2419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Iten E., Ziemiecki A., Schäfer R. The transformation-suppressive function is lost in tumorigenic cells and is restored upon transfer of a suppressor gene. Recent Results Cancer Res. 1989;113:78–89. doi: 10.1007/978-3-642-83638-1_10. [DOI] [PubMed] [Google Scholar]
  11. Klein G. The approaching era of the tumor suppressor genes. Science. 1987 Dec 11;238(4833):1539–1545. doi: 10.1126/science.3317834. [DOI] [PubMed] [Google Scholar]
  12. Klemenz R., Fröhli E., Aoyama A., Hoffmann S., Simpson R. J., Moritz R. L., Schäfer R. Alpha B crystallin accumulation is a specific response to Ha-ras and v-mos oncogene expression in mouse NIH 3T3 fibroblasts. Mol Cell Biol. 1991 Feb;11(2):803–812. doi: 10.1128/mcb.11.2.803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Klemenz R., Hoffmann S., Jaggi R., Werenskiold A. K. The v-mos and c-Ha-ras oncoproteins exert similar effects on the pattern of protein synthesis. Oncogene. 1989 Jun;4(6):799–803. [PubMed] [Google Scholar]
  14. Klemenz R., Hoffmann S., Werenskiold A. K. Serum- and oncoprotein-mediated induction of a gene with sequence similarity to the gene encoding carcinoembryonic antigen. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5708–5712. doi: 10.1073/pnas.86.15.5708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Krönke M., Schlüter C., Pfizenmaier K. Tumor necrosis factor inhibits MYC expression in HL-60 cells at the level of mRNA transcription. Proc Natl Acad Sci U S A. 1987 Jan;84(2):469–473. doi: 10.1073/pnas.84.2.469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kuzumaki N., Ogiso Y., Oda A., Fujita H., Suzuki H., Sato C., Müllauer L. Resistance to oncogenic transformation in revertant R1 of human ras-transformed NIH 3T3 cells. Mol Cell Biol. 1989 May;9(5):2258–2263. doi: 10.1128/mcb.9.5.2258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Noda M., Kitayama H., Matsuzaki T., Sugimoto Y., Okayama H., Bassin R. H., Ikawa Y. Detection of genes with a potential for suppressing the transformed phenotype associated with activated ras genes. Proc Natl Acad Sci U S A. 1989 Jan;86(1):162–166. doi: 10.1073/pnas.86.1.162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Ostertag W., Seliger B., Kollek R., Stocking C., Bergholz U., Smadja-Joffe F. The myeloproliferative sarcoma virus retains transforming functions after introduction of a dominant selectable marker gene. J Gen Virol. 1986 Jul;67(Pt 7):1361–1371. doi: 10.1099/0022-1317-67-7-1361. [DOI] [PubMed] [Google Scholar]
  20. Pestka S., Langer J. A., Zoon K. C., Samuel C. E. Interferons and their actions. Annu Rev Biochem. 1987;56:727–777. doi: 10.1146/annurev.bi.56.070187.003455. [DOI] [PubMed] [Google Scholar]
  21. Redmond S. M., Reichmann E., Müller R. G., Friis R. R., Groner B., Hynes N. E. The transformation of primary and established mouse mammary epithelial cells by p21-ras is concentration dependent. Oncogene. 1988 Mar;2(3):259–265. [PubMed] [Google Scholar]
  22. Rimoldi D., Samid D., Flessate D. M., Friedman R. M. Transcriptional inhibition of Ha-ras in interferon-induced revertants of ras-transformed mouse cells. Cancer Res. 1988 Sep 15;48(18):5157–5162. [PubMed] [Google Scholar]
  23. 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]
  24. 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]
  25. Samid D., Flessate D. M., Friedman R. M. Interferon-induced revertants of ras-transformed cells: resistance to transformation by specific oncogenes and retransformation by 5-azacytidine. Mol Cell Biol. 1987 Jun;7(6):2196–2200. doi: 10.1128/mcb.7.6.2196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schaefer R., Iyer J., Iten E., Nirkko A. C. Partial reversion of the transformed phenotype in HRAS-transfected tumorigenic cells by transfer of a human gene. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1590–1594. doi: 10.1073/pnas.85.5.1590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Schäfer R., Hoffmann H., Willecke K. Suppression of tumorigenicity in hybrids of tumorigenic Chinese hamster cells and diploid mouse fibroblasts: dependence on the presence of at least three different mouse chromosomes and independence of hamster genome dosage. Cancer Res. 1983 May;43(5):2240–2246. [PubMed] [Google Scholar]
  28. Seliger B., Kruppa G., Pfizenmaier K. Murine gamma interferon inhibits v-mos-induced fibroblast transformation via down regulation of retroviral gene expression. J Virol. 1987 Aug;61(8):2567–2572. doi: 10.1128/jvi.61.8.2567-2572.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Seliger B., Kruppa G., Schäfer R., Redmond S. M., Pfizenmaier K. Gamma interferon regulates long terminal repeat-controlled oncogene expression in transformed mouse fibroblasts at the level of mRNA transcription. J Virol. 1988 Feb;62(2):619–621. doi: 10.1128/jvi.62.2.619-621.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sergiescu D., Gerfaux J., Joret A. M., Chany C. Persistent expression of v-mos oncogene in transformed cells that revert to nonmalignancy after prolonged treatment with interferon. Proc Natl Acad Sci U S A. 1986 Aug;83(16):5764–5768. doi: 10.1073/pnas.83.16.5764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Smith M. R., DeGudicibus S. J., Stacey D. W. Requirement for c-ras proteins during viral oncogene transformation. Nature. 1986 Apr 10;320(6062):540–543. doi: 10.1038/320540a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Wigler M., Pellicer A., Silverstein S., Axel R. Biochemical transfer of single-copy eucaryotic genes using total cellular DNA as donor. Cell. 1978 Jul;14(3):725–731. doi: 10.1016/0092-8674(78)90254-4. [DOI] [PubMed] [Google Scholar]
  33. Yanagihara K., Ciardiello F., Talbot N., McGeady M. L., Cooper H., Benade L., Salomon D. S., Bassin R. H. Isolation of a new class of 'flat' revertants from ras-transformed NIH3T3 cells using cis-4-hydroxy-L-proline. Oncogene. 1990 Aug;5(8):1179–1186. [PubMed] [Google Scholar]
  34. Zarbl H., Latreille J., Jolicoeur P. Revertants of v-fos-transformed fibroblasts have mutations in cellular genes essential for transformation by other oncogenes. Cell. 1987 Nov 6;51(3):357–369. doi: 10.1016/0092-8674(87)90632-5. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES