Skip to main content
The EMBO Journal logoLink to The EMBO Journal
. 1986 Oct;5(10):2609–2616. doi: 10.1002/j.1460-2075.1986.tb04541.x

The v-mos and H-ras oncogene expression represses glucocorticoid hormone-dependent transcription from the mouse mammary tumor virus LTR.

R Jaggi, B Salmons, D Muellener, B Groner
PMCID: PMC1167159  PMID: 3023051

Abstract

We have subjected the viral mos oncogene (v-mos), the activated human H-ras oncogene [H-ras (A)] and the normal human H-ras protooncogene [H-ras (N)] to the transcriptional regulation of glucocorticoid hormones by in vitro recombination with the promoter region of the mouse mammary tumor virus long terminal repeat (MMTV LTR) and transfection into NIH 3T3 cells. Cell clones were selected which exhibit a transformed phenotype strictly dependent on the presence of hormone in the growth medium. The expression of the chimeric genes as a function of time after hormone stimulation was studied at the level of transcriptional rate, mRNA and protein accumulation. Oncogene expression was stimulated rapidly to high levels, after hormone addition, but declined in the continuous presence of hormone. Measurements of the transcriptional rates in nuclei from LTR v-mos and LTR H-ras (A) transfected cells showed a repression of LTR v-mos and LTR H-ras (A) transcription after the initial stimulation by hormone. LTR H-ras (N) transcription was not affected. An independently transfected LTR H-2Ld construct in LTR v-mos or LTR H-ras (A) containing cells is also transcriptionally repressed. These experiments demonstrated a transcriptional repression effect of the oncogene products on the glucocorticoid hormone-dependent MMTV LTR transcription.

Full text

PDF
2609

Images in this article

Selected References

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

  1. Andres A. C., Muellener D. B., Ryffel G. U. Persistence, methylation and expression of vitellogenin gene derivatives after injection into fertilized eggs of Xenopus laevis. Nucleic Acids Res. 1984 Mar 12;12(5):2283–2302. doi: 10.1093/nar/12.5.2283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Blanchardie P., Lustenberger P., Orsonneau J. L., Denis M., Bernard S. Influence of molybdate, ionic strength and pH on ligand binding to the glucocorticoid receptor. Steroids. 1984 Aug;44(2):159–174. doi: 10.1016/s0039-128x(84)90088-6. [DOI] [PubMed] [Google Scholar]
  3. Blochlinger K., Diggelmann H. Hygromycin B phosphotransferase as a selectable marker for DNA transfer experiments with higher eucaryotic cells. Mol Cell Biol. 1984 Dec;4(12):2929–2931. doi: 10.1128/mcb.4.12.2929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Borrelli E., Hen R., Chambon P. Adenovirus-2 E1A products repress enhancer-induced stimulation of transcription. Nature. 1984 Dec 13;312(5995):608–612. doi: 10.1038/312608a0. [DOI] [PubMed] [Google Scholar]
  5. Brawerman G., Mendecki J., Lee S. Y. A procedure for the isolation of mammalian messenger ribonucleic acid. Biochemistry. 1972 Feb 15;11(4):637–641. doi: 10.1021/bi00754a027. [DOI] [PubMed] [Google Scholar]
  6. Buetti E., Diggelmann H. Glucocorticoid regulation of mouse mammary tumor virus: identification of a short essential DNA region. EMBO J. 1983;2(8):1423–1429. doi: 10.1002/j.1460-2075.1983.tb01601.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Capon D. J., Chen E. Y., Levinson A. D., Seeburg P. H., Goeddel D. V. Complete nucleotide sequences of the T24 human bladder carcinoma oncogene and its normal homologue. Nature. 1983 Mar 3;302(5903):33–37. doi: 10.1038/302033a0. [DOI] [PubMed] [Google Scholar]
  8. Chapman A. B., Costello M. A., Lee F., Ringold G. M. Amplification and hormone-regulated expression of a mouse mammary tumor virus-Eco gpt fusion plasmid in mouse 3T6 cells. Mol Cell Biol. 1983 Aug;3(8):1421–1429. doi: 10.1128/mcb.3.8.1421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fasel N., Pearson K., Buetti E., Diggelmann H. The region of mouse mammary tumor virus DNA containing the long terminal repeat includes a long coding sequence and signals for hormonally regulated transcription. EMBO J. 1982;1(1):3–7. doi: 10.1002/j.1460-2075.1982.tb01115.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Garry R. F., Moyer M. P., Bishop J. M., Moyer R. C., Waite M. R. Transformation parameters induced in chick cells by incubation in media of altered NaCl concentration. Virology. 1981 Jun;111(2):427–439. doi: 10.1016/0042-6822(81)90346-9. [DOI] [PubMed] [Google Scholar]
  11. Gilman A. G. G proteins and dual control of adenylate cyclase. Cell. 1984 Mar;36(3):577–579. doi: 10.1016/0092-8674(84)90336-2. [DOI] [PubMed] [Google Scholar]
  12. Groner B., Hynes N. E., Diggelmann H. Identification of mouse mammary tumor virus-specific mRNA. J Virol. 1979 Apr;30(1):417–420. doi: 10.1128/jvi.30.1.417-420.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Groner B., Hynes N. E., Rahmsdorf U., Ponta H. Transcription initiation of transfected mouse mammary tumor virus LTR DNA is regulated by glucocorticoid hormones. Nucleic Acids Res. 1983 Jul 25;11(14):4713–4725. doi: 10.1093/nar/11.14.4713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hen R., Borrelli E., Chambon P. Repression of the immunoglobulin heavy chain enhancer by the adenovirus-2 E1A products. Science. 1985 Dec 20;230(4732):1391–1394. doi: 10.1126/science.2999984. [DOI] [PubMed] [Google Scholar]
  15. Hendricks M., Weintraub H. Multiple tropomyosin polypeptides in chicken embryo fibroblasts: differential repression of transcription by Rous sarcoma virus transformation. Mol Cell Biol. 1984 Sep;4(9):1823–1833. doi: 10.1128/mcb.4.9.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Housley P. R., Pratt W. B. Direct demonstration of glucocorticoid receptor phosphorylation by intact L-cells. J Biol Chem. 1983 Apr 10;258(7):4630–4635. [PubMed] [Google Scholar]
  17. Huang A. L., Ostrowski M. C., Berard D., Hager G. L. Glucocorticoid regulation of the Ha-MuSV p21 gene conferred by sequences from mouse mammary tumor virus. Cell. 1981 Dec;27(2 Pt 1):245–255. doi: 10.1016/0092-8674(81)90408-6. [DOI] [PubMed] [Google Scholar]
  18. Hynes N., van Ooyen A. J., Kennedy N., Herrlich P., Ponta H., Groner B. Subfragments of the large terminal repeat cause glucocorticoid-responsive expression of mouse mammary tumor virus and of an adjacent gene. Proc Natl Acad Sci U S A. 1983 Jun;80(12):3637–3641. doi: 10.1073/pnas.80.12.3637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jakobovits E. B., Majors J. E., Varmus H. E. Hormonal regulation of the Rous sarcoma virus src gene via a heterologous promoter defines a threshold dose for cellular transformation. Cell. 1984 Oct;38(3):757–765. doi: 10.1016/0092-8674(84)90271-x. [DOI] [PubMed] [Google Scholar]
  20. Karin M., Haslinger A., Holtgreve H., Richards R. I., Krauter P., Westphal H. M., Beato M. Characterization of DNA sequences through which cadmium and glucocorticoid hormones induce human metallothionein-IIA gene. Nature. 1984 Apr 5;308(5959):513–519. doi: 10.1038/308513a0. [DOI] [PubMed] [Google Scholar]
  21. Kingston R. E., Baldwin A. S., Sharp P. A. Transcription control by oncogenes. Cell. 1985 May;41(1):3–5. doi: 10.1016/0092-8674(85)90049-2. [DOI] [PubMed] [Google Scholar]
  22. Koblinsky M., Beato M., Kalimi M., Feigelson P. Glucocorticoid-binding proteins of rat liver cytosol. II. Physical characterization and properties of the binding proteins. J Biol Chem. 1972 Dec 25;247(24):7897–7904. [PubMed] [Google Scholar]
  23. Majors J., Varmus H. E. A small region of the mouse mammary tumor virus long terminal repeat confers glucocorticoid hormone regulation on a linked heterologous gene. Proc Natl Acad Sci U S A. 1983 Oct;80(19):5866–5870. doi: 10.1073/pnas.80.19.5866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Matrisian L. M., Glaichenhaus N., Gesnel M. C., Breathnach R. Epidermal growth factor and oncogenes induce transcription of the same cellular mRNA in rat fibroblasts. EMBO J. 1985 Jun;4(6):1435–1440. doi: 10.1002/j.1460-2075.1985.tb03799.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Maxwell S. A., Arlinghaus R. B. Serine kinase activity associated with Maloney murine sarcoma virus-124-encoded p37mos. Virology. 1985 May;143(1):321–333. doi: 10.1016/0042-6822(85)90119-9. [DOI] [PubMed] [Google Scholar]
  26. McKnight G. S., Palmiter R. D. Transcriptional regulation of the ovalbumin and conalbumin genes by steroid hormones in chick oviduct. J Biol Chem. 1979 Sep 25;254(18):9050–9058. [PubMed] [Google Scholar]
  27. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Papkoff J., Nigg E. A., Hunter T. The transforming protein of Moloney murine sarcoma virus is a soluble cytoplasmic protein. Cell. 1983 May;33(1):161–172. doi: 10.1016/0092-8674(83)90345-8. [DOI] [PubMed] [Google Scholar]
  29. Papkoff J., Ringold G. M. Use of the mouse mammary tumor virus long terminal repeat to promote steroid-inducible expression of v-mos. J Virol. 1984 Nov;52(2):420–430. doi: 10.1128/jvi.52.2.420-430.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Payvar F., DeFranco D., Firestone G. L., Edgar B., Wrange O., Okret S., Gustafsson J. A., Yamamoto K. R. Sequence-specific binding of glucocorticoid receptor to MTV DNA at sites within and upstream of the transcribed region. Cell. 1983 Dec;35(2 Pt 1):381–392. doi: 10.1016/0092-8674(83)90171-x. [DOI] [PubMed] [Google Scholar]
  31. Ponta H., Ball R., Steinmetz M., Groner B. Hormonal regulation of cell surface expression of the major histocompatibility antigen H-2Ld in transfected cells. EMBO J. 1985 Dec 16;4(13A):3447–3453. doi: 10.1002/j.1460-2075.1985.tb04103.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ponta H., Günzburg W. H., Salmons B., Groner B., Herrlich P. Mouse mammary tumour virus: a proviral gene contributes to the understanding of eukaryotic gene expression and mammary tumorigenesis. J Gen Virol. 1985 May;66(Pt 5):931–943. doi: 10.1099/0022-1317-66-5-931. [DOI] [PubMed] [Google Scholar]
  33. Ponta H., Kennedy N., Herrlich P., Hynes N. E., Groner B. A deletion mutant of mouse mammary tumour virus, lacking 516 nucleotides of the 5' long terminal repeat sequence, can be expressed in a hormone-responsive fashion. J Gen Virol. 1983 Mar;64(Pt 3):567–577. doi: 10.1099/0022-1317-64-3-567. [DOI] [PubMed] [Google Scholar]
  34. Ponta H., Kennedy N., Skroch P., Hynes N. E., Groner B. Hormonal response region in the mouse mammary tumor virus long terminal repeat can be dissociated from the proviral promoter and has enhancer properties. Proc Natl Acad Sci U S A. 1985 Feb;82(4):1020–1024. doi: 10.1073/pnas.82.4.1020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Renkawitz R., Schütz G., von der Ahe D., Beato M. Sequences in the promoter region of the chicken lysozyme gene required for steroid regulation and receptor binding. Cell. 1984 Jun;37(2):503–510. doi: 10.1016/0092-8674(84)90380-5. [DOI] [PubMed] [Google Scholar]
  36. Ringold G. M., Cardiff R. D., Varmus H. E., Yamamoto K. R. Infection of cultured rat hepatoma cells by mouse mammary tumor virus. Cell. 1977 Jan;10(1):11–18. doi: 10.1016/0092-8674(77)90134-9. [DOI] [PubMed] [Google Scholar]
  37. Rosenthal A., Wright S., Quade K., Gallimore P., Cedar H., Grosveld F. Increased MHC H-2K gene transcription in cultured mouse embryo cells after adenovirus infection. Nature. 1985 Jun 13;315(6020):579–581. doi: 10.1038/315579a0. [DOI] [PubMed] [Google Scholar]
  38. Roth D. B., Wilson J. H. Relative rates of homologous and nonhomologous recombination in transfected DNA. Proc Natl Acad Sci U S A. 1985 May;82(10):3355–3359. doi: 10.1073/pnas.82.10.3355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sandmeyer S., Gallis B., Bornstein P. Coordinate transcriptional regulation of type I procollagen genes by Rous sarcoma virus. J Biol Chem. 1981 May 25;256(10):5022–5028. [PubMed] [Google Scholar]
  40. Schmidt A., Setoyama C., de Crombrugghe B. Regulation of a collagen gene promoter by the product of viral mos oncogene. Nature. 1985 Mar 21;314(6008):286–289. doi: 10.1038/314286a0. [DOI] [PubMed] [Google Scholar]
  41. Schöler H. R., Gruss P. Specific interaction between enhancer-containing molecules and cellular components. Cell. 1984 Feb;36(2):403–411. doi: 10.1016/0092-8674(84)90233-2. [DOI] [PubMed] [Google Scholar]
  42. Scott M. R., Westphal K. H., Rigby P. W. Activation of mouse genes in transformed cells. Cell. 1983 Sep;34(2):557–567. doi: 10.1016/0092-8674(83)90388-4. [DOI] [PubMed] [Google Scholar]
  43. Setoyama C., Liau G., de Crombrugghe B. Pleiotropic mutants of NIH 3T3 cells with altered regulation in the expression of both type I collagen and fibronectin. Cell. 1985 May;41(1):201–209. doi: 10.1016/0092-8674(85)90074-1. [DOI] [PubMed] [Google Scholar]
  44. Shih T. Y., Weeks M. O., Gruss P., Dhar R., Oroszlan S., Scolnick E. M. Identification of a precursor in the biosynthesis of the p21 transforming protein of harvey murine sarcoma virus. J Virol. 1982 Apr;42(1):253–261. doi: 10.1128/jvi.42.1.253-261.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Singh V. B., Moudgil V. K. Phosphorylation of rat liver glucocorticoid receptor. J Biol Chem. 1985 Mar 25;260(6):3684–3690. [PubMed] [Google Scholar]
  46. Slater E. P., Rabenau O., Karin M., Baxter J. D., Beato M. Glucocorticoid receptor binding and activation of a heterologous promoter by dexamethasone by the first intron of the human growth hormone gene. Mol Cell Biol. 1985 Nov;5(11):2984–2992. doi: 10.1128/mcb.5.11.2984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. 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]
  48. Stein R., Ziff E. B. HeLa cell beta-tubulin gene transcription is stimulated by adenovirus 5 in parallel with viral early genes by an E1a-dependent mechanism. Mol Cell Biol. 1984 Dec;4(12):2792–2801. doi: 10.1128/mcb.4.12.2792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Tyagi J. S., Hirano H., Merlino G. T., Pastan I. Transcriptional control of the fibronectin gene in chick embryo fibroblasts transformed by Rous sarcoma virus. J Biol Chem. 1983 May 10;258(9):5787–5793. [PubMed] [Google Scholar]
  50. Ulsh L. S., Shih T. Y. Metabolic turnover of human c-rasH p21 protein of EJ bladder carcinoma and its normal cellular and viral homologs. Mol Cell Biol. 1984 Aug;4(8):1647–1652. doi: 10.1128/mcb.4.8.1647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Van Beveren C., van Straaten F., Galleshaw J. A., Verma I. M. Nucleotide sequence of the genome of a murine sarcoma virus. Cell. 1981 Nov;27(1 Pt 2):97–108. doi: 10.1016/0092-8674(81)90364-0. [DOI] [PubMed] [Google Scholar]
  52. Velcich A., Ziff E. Adenovirus E1a proteins repress transcription from the SV40 early promoter. Cell. 1985 Mar;40(3):705–716. doi: 10.1016/0092-8674(85)90219-3. [DOI] [PubMed] [Google Scholar]
  53. Weinberger C., Hollenberg S. M., Rosenfeld M. G., Evans R. M. Domain structure of human glucocorticoid receptor and its relationship to the v-erb-A oncogene product. Nature. 1985 Dec 19;318(6047):670–672. doi: 10.1038/318670a0. [DOI] [PubMed] [Google Scholar]
  54. Wigler M., Sweet R., Sim G. K., Wold B., Pellicer A., Lacy E., Maniatis T., Silverstein S., Axel R. Transformation of mammalian cells with genes from procaryotes and eucaryotes. Cell. 1979 Apr;16(4):777–785. doi: 10.1016/0092-8674(79)90093-x. [DOI] [PubMed] [Google Scholar]
  55. van der Hoorn F. A., Müller V. Differential transformation of C3H10T1/2 cells by v-mos: sequential expression of transformation parameters. Mol Cell Biol. 1985 Sep;5(9):2204–2211. doi: 10.1128/mcb.5.9.2204. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES