Skip to main content
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1991 May;11(5):2529–2537. doi: 10.1128/mcb.11.5.2529

Two regions of the mouse mammary tumor virus long terminal repeat regulate the activity of its promoter in mammary cell lines.

P Lefebvre 1, D S Berard 1, M G Cordingley 1, G L Hager 1
PMCID: PMC360022  PMID: 1708094

Abstract

In vivo expression of the mouse mammary tumor virus (MMTV) is restricted to a few organs, with the highest rate of transcription found in the mammary gland. Using a series of mammary and nonmammary murine cell lines, we have identified two regulatory elements, located upstream of the hormone responsive element, that specifically regulate the MMTV promoter. The first element displays an enhancerlike activity and is coincident with the binding of a nuclear factor (designated MP4; position -1078 to -1052 in the long terminal repeat) whose presence is apparently restricted to mammary cell lines. The second regulatory region mediates a repressive activity and is mapped to the long terminal repeat segment from -415 to -483. This repression is specific for a particular subtype of mammary cells (RAC cells) able to grow under two differentiation states (A. Sonnenberg, H. Daams, J. Calafat, and J. Hilgers, Cancer Res. 46:5913-5922, 1986). The MMTV promoter in mammary cell lines thus appears to be modulated by two cis-acting elements that are likely to be involved in tissue-specific expression in vivo.

Full text

PDF
2532

Images in this article

Selected References

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

  1. Ball J. K., Diggelmann H., Dekaban G. A., Grossi G. F., Semmler R., Waight P. A., Fletcher R. F. Alterations in the U3 region of the long terminal repeat of an infectious thymotropic type B retrovirus. J Virol. 1988 Aug;62(8):2985–2993. doi: 10.1128/jvi.62.8.2985-2993.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  3. Breznik T., Traina-Dorge V., Gama-Sosa M., Gehrke C. W., Ehrlich M., Medina D., Butel J. S., Cohen J. C. Mouse mammary tumor virus DNA methylation: tissue-specific variation. Virology. 1984 Jul 15;136(1):69–77. doi: 10.1016/0042-6822(84)90248-4. [DOI] [PubMed] [Google Scholar]
  4. Buetti E., Kühnel B., Diggelmann H. Dual function of a nuclear factor I binding site in MMTV transcription regulation. Nucleic Acids Res. 1989 Apr 25;17(8):3065–3078. doi: 10.1093/nar/17.8.3065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cato A. C., Skroch P., Weinmann J., Butkeraitis P., Ponta H. DNA sequences outside the receptor-binding sites differently modulate the responsiveness of the mouse mammary tumour virus promoter to various steroid hormones. EMBO J. 1988 May;7(5):1403–1410. doi: 10.1002/j.1460-2075.1988.tb02957.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cohen J. C. Methylation of milk-borne and genetically transmitted mouse mammary tumor virus proviral DNA. Cell. 1980 Mar;19(3):653–662. doi: 10.1016/s0092-8674(80)80042-0. [DOI] [PubMed] [Google Scholar]
  7. Cordingley M. G., Riegel A. T., Hager G. L. Steroid-dependent interaction of transcription factors with the inducible promoter of mouse mammary tumor virus in vivo. Cell. 1987 Jan 30;48(2):261–270. doi: 10.1016/0092-8674(87)90429-6. [DOI] [PubMed] [Google Scholar]
  8. Darbre P., King R. J. Progression to steroid autonomy in S115 mouse mammary tumor cells: role of DNA methylation. J Cell Biol. 1984 Oct;99(4 Pt 1):1410–1415. doi: 10.1083/jcb.99.4.1410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dickson C. Molecular aspects of mouse mammary tumor virus biology. Int Rev Cytol. 1987;108:119–147. doi: 10.1016/s0074-7696(08)61437-0. [DOI] [PubMed] [Google Scholar]
  10. Dickson C., Smith R., Brookes S., Peters G. Proviral insertions within the int-2 gene can generate multiple anomalous transcripts but leave the protein-coding domain intact. J Virol. 1990 Feb;64(2):784–793. doi: 10.1128/jvi.64.2.784-793.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dickson C., Smith R., Brookes S., Peters G. Tumorigenesis by mouse mammary tumor virus: proviral activation of a cellular gene in the common integration region int-2. Cell. 1984 Jun;37(2):529–536. doi: 10.1016/0092-8674(84)90383-0. [DOI] [PubMed] [Google Scholar]
  12. Dignam J. D., Martin P. L., Shastry B. S., Roeder R. G. Eukaryotic gene transcription with purified components. Methods Enzymol. 1983;101:582–598. doi: 10.1016/0076-6879(83)01039-3. [DOI] [PubMed] [Google Scholar]
  13. Donehower L. A., Andre J., Berard D. S., Wolford R. G., Hager G. L. Construction and characterization of molecular clones containing integrated mouse mammary tumor virus sequences. Cold Spring Harb Symp Quant Biol. 1980;44(Pt 2):1153–1159. doi: 10.1101/sqb.1980.044.01.124. [DOI] [PubMed] [Google Scholar]
  14. Donehower L. A., Huang A. L., Hager G. L. Regulatory and coding potential of the mouse mammary tumor virus long terminal redundancy. J Virol. 1981 Jan;37(1):226–238. doi: 10.1128/jvi.37.1.226-238.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Eisen H. J., Schleenbaker R. E., Simons S. S., Jr Affinity labeling of the rat liver glucocorticoid receptor with dexamethasone 21-mesylate. Identification of covalently labeled receptor by immunochemical methods. J Biol Chem. 1981 Dec 25;256(24):12920–12925. [PubMed] [Google Scholar]
  16. Garcia M., Wellinger R., Vessaz A., Diggelmann H. A new site of integration for mouse mammary tumor virus proviral DNA common to BALB/cf(C3H) mammary and kidney adenocarcinomas. EMBO J. 1986 Jan;5(1):127–134. doi: 10.1002/j.1460-2075.1986.tb04186.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Günzburg W. H., Hynes N. E., Groner B. The methylation pattern of endogenous mouse mammary tumor virus proviral genes is tissue specific and stably inherited. Virology. 1984 Oct 30;138(2):212–224. doi: 10.1016/0042-6822(84)90346-5. [DOI] [PubMed] [Google Scholar]
  18. Hager G. L. MMTV as a model for gene expression in mammary tissue. Cancer Treat Res. 1988;40:267–281. doi: 10.1007/978-1-4613-1733-3_13. [DOI] [PubMed] [Google Scholar]
  19. Henrard D., Ross S. R. Endogenous mouse mammary tumor virus is expressed in several organs in addition to the lactating mammary gland. J Virol. 1988 Aug;62(8):3046–3049. doi: 10.1128/jvi.62.8.3046-3049.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hsu C. L., Fabritius C., Dudley J. Mouse mammary tumor virus proviruses in T-cell lymphomas lack a negative regulatory element in the long terminal repeat. J Virol. 1988 Dec;62(12):4644–4652. doi: 10.1128/jvi.62.12.4644-4652.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kuwabara M. D., Sigman D. S. Footprinting DNA-protein complexes in situ following gel retardation assays using 1,10-phenanthroline-copper ion: Escherichia coli RNA polymerase-lac promoter complexes. Biochemistry. 1987 Nov 17;26(23):7234–7238. doi: 10.1021/bi00397a006. [DOI] [PubMed] [Google Scholar]
  22. Langer S. J., Ostrowski M. C. Negative regulation of transcription in vitro by a glucocorticoid response element is mediated by a trans-acting factor. Mol Cell Biol. 1988 Sep;8(9):3872–3881. doi: 10.1128/mcb.8.9.3872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lefebvre P., Danze P. M., Sablonniere B., Richard C., Formstecher P., Dautrevaux M. Association of the glucocorticoid receptor binding subunit with the 90K nonsteroid-binding component is stabilized by both steroidal and nonsteroidal antiglucocorticoids in intact cells. Biochemistry. 1988 Dec 27;27(26):9186–9194. doi: 10.1021/bi00426a017. [DOI] [PubMed] [Google Scholar]
  24. Matsui Y., Halter S. A., Holt J. T., Hogan B. L., Coffey R. J. Development of mammary hyperplasia and neoplasia in MMTV-TGF alpha transgenic mice. Cell. 1990 Jun 15;61(6):1147–1155. doi: 10.1016/0092-8674(90)90077-r. [DOI] [PubMed] [Google Scholar]
  25. Michalides R., Wagenaar E. Site-specific rearrangements in the long terminal repeat of extra mouse mammary tumor proviruses in murine T-cell leukemias. Virology. 1986 Oct 15;154(1):76–84. doi: 10.1016/0042-6822(86)90431-9. [DOI] [PubMed] [Google Scholar]
  26. Michalides R., Wagenaar E., Weijers P. Rearrangements in the long terminal repeat of extra mouse mammary tumor proviruses in T-cell leukemias of mouse strain GR result in a novel enhancer-like structure. Mol Cell Biol. 1985 Apr;5(4):823–830. doi: 10.1128/mcb.5.4.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Miksicek R., Borgmeyer U., Nowock J. Interaction of the TGGCA-binding protein with upstream sequences is required for efficient transcription of mouse mammary tumor virus. EMBO J. 1987 May;6(5):1355–1360. doi: 10.1002/j.1460-2075.1987.tb02375.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mink S., Ponta H., Cato A. C. The long terminal repeat region of the mouse mammary tumour virus contains multiple regulatory elements. Nucleic Acids Res. 1990 Apr 25;18(8):2017–2024. doi: 10.1093/nar/18.8.2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Moore R., Casey G., Brookes S., Dixon M., Peters G., Dickson C. Sequence, topography and protein coding potential of mouse int-2: a putative oncogene activated by mouse mammary tumour virus. EMBO J. 1986 May;5(5):919–924. doi: 10.1002/j.1460-2075.1986.tb04304.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Morley K. L., Toohey M. G., Peterson D. O. Transcriptional repression of a hormone-responsive promoter. Nucleic Acids Res. 1987 Sep 11;15(17):6973–6989. doi: 10.1093/nar/15.17.6973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Muller W. J., Lee F. S., Dickson C., Peters G., Pattengale P., Leder P. The int-2 gene product acts as an epithelial growth factor in transgenic mice. EMBO J. 1990 Mar;9(3):907–913. doi: 10.1002/j.1460-2075.1990.tb08188.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Nordeen S. K. Luciferase reporter gene vectors for analysis of promoters and enhancers. Biotechniques. 1988 May;6(5):454–458. [PubMed] [Google Scholar]
  33. Nusse R. The int genes in mammary tumorigenesis and in normal development. Trends Genet. 1988 Oct;4(10):291–295. doi: 10.1016/0168-9525(88)90172-2. [DOI] [PubMed] [Google Scholar]
  34. Nusse R., Theunissen H., Wagenaar E., Rijsewijk F., Gennissen A., Otte A., Schuuring E., van Ooyen A. The Wnt-1 (int-1) oncogene promoter and its mechanism of activation by insertion of proviral DNA of the mouse mammary tumor virus. Mol Cell Biol. 1990 Aug;10(8):4170–4179. doi: 10.1128/mcb.10.8.4170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Nusse R., van Ooyen A., Cox D., Fung Y. K., Varmus H. Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15. Nature. 1984 Jan 12;307(5947):131–136. doi: 10.1038/307131a0. [DOI] [PubMed] [Google Scholar]
  36. Ostrowski M. C., Richard-Foy H., Wolford R. G., Berard D. S., Hager G. L. Glucocorticoid regulation of transcription at an amplified, episomal promoter. Mol Cell Biol. 1983 Nov;3(11):2045–2057. doi: 10.1128/mcb.3.11.2045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Parks W. P., Hubbell E. S., Goldberg R. J., O'Neill F. J., Scolnick E. M. High frequency variation in mammary tumor virus expression in cell culture. Cell. 1976 May;8(1):87–93. doi: 10.1016/0092-8674(76)90189-6. [DOI] [PubMed] [Google Scholar]
  38. Pattengale P. K., Stewart T. A., Leder A., Sinn E., Muller W., Tepler I., Schmidt E., Leder P. Animal models of human disease. Pathology and molecular biology of spontaneous neoplasms occurring in transgenic mice carrying and expressing activated cellular oncogenes. Am J Pathol. 1989 Jul;135(1):39–61. [PMC free article] [PubMed] [Google Scholar]
  39. Ross S. R., Solter D. Glucocorticoid regulation of mouse mammary tumor virus sequences in transgenic mice. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5880–5884. doi: 10.1073/pnas.82.17.5880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Simons S. S., Jr, Schleenbaker R. E., Eisen H. J. Activation of covalent affinity labeled glucocorticoid receptor-steroid complexes. J Biol Chem. 1983 Feb 25;258(4):2229–2238. [PubMed] [Google Scholar]
  41. Sonnenberg A., Daams H., Calafat J., Hilgers J. In vitro differentiation and progression of mouse mammary tumor cells. Cancer Res. 1986 Nov;46(11):5913–5922. [PubMed] [Google Scholar]
  42. Sonnenberg A., van Balen P., Hilgers J., Schuuring E., Nusse R. Oncogene expression during progression of mouse mammary tumor cells; activity of a proviral enhancer and the resulting expression of int-2 is influenced by the state of differentiation. EMBO J. 1987 Jan;6(1):121–125. doi: 10.1002/j.1460-2075.1987.tb04728.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Stewart T. A., Hollingshead P. G., Pitts S. L. Multiple regulatory domains in the mouse mammary tumor virus long terminal repeat revealed by analysis of fusion genes in transgenic mice. Mol Cell Biol. 1988 Jan;8(1):473–479. doi: 10.1128/mcb.8.1.473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wellinger R. J., Garcia M., Vessaz A., Diggelmann H. Exogenous mouse mammary tumor virus proviral DNA isolated from a kidney adenocarcinoma cell line contains alterations in the U3 region of the long terminal repeat. J Virol. 1986 Oct;60(1):1–11. doi: 10.1128/jvi.60.1.1-11.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. 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]
  46. Yanagawa S., Murakami A., Tanaka H. Extra mouse mammary tumor proviruses in DBA/2 mouse lymphomas acquire a selective advantage in lymphocytes by alteration in the U3 region of the long terminal repeat. J Virol. 1990 Jun;64(6):2474–2483. doi: 10.1128/jvi.64.6.2474-2483.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. de Wet J. R., Wood K. V., DeLuca M., Helinski D. R., Subramani S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol. 1987 Feb;7(2):725–737. doi: 10.1128/mcb.7.2.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. van Ooyen A., Nusse R. Structure and nucleotide sequence of the putative mammary oncogene int-1; proviral insertions leave the protein-encoding domain intact. Cell. 1984 Nov;39(1):233–240. doi: 10.1016/0092-8674(84)90209-5. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES