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. 1990 Apr 25;18(8):2017–2024. doi: 10.1093/nar/18.8.2017

The long terminal repeat region of the mouse mammary tumour virus contains multiple regulatory elements.

S Mink 1, H Ponta 1, A C Cato 1
PMCID: PMC330677  PMID: 2159634

Abstract

Mouse mammary tumour virus (MMTV) is the major aetiologic agent of mouse mammary tumour formation. The expression of this virus is regulated by steroid hormones and cell type specific factors. The nucleotide sequence that controls the steroid hormone response has already been localized between -202 and -59 upstream of the start of transcription in the long terminal repeat (LTR) region of the proviral DNA. Through transfection experiments in three different cultured mouse cell lines (NIH3T3, NMuMG and GR), we have investigated which sequences in the MMTV LTR play a role in the cell type specific expression at the proviral promoter. We have identified two elements on the MMTV LTR from -631 to -560 and from -428 to -364 that have the potential to influence expression at the MMTV LTR promoter. The -631 to -560 element mediated a negative response in all the cell types we studied whereas the -428 to -364 element had negative effects in the mouse fibroblast NIH3T3 and the normal mouse mammary gland cell NMuMG but not in the mouse mammary tumour epithelial GR cells. The -428 to -364 element therefore contributes to the cell type specific expression at MMTV LTR promoter. We have also identified another regulatory element between -1094 and -739 that had a slight positive regulatory effect at the MMTV LTR promoter but greatly enhanced expression at a foreign promoter when present at this promoter in an orientation that is the reverse of its own orientation in the MMTV LTR. This orientation-dependent effect was only observed in the mouse mammary epithelial cells NMuMG and GR but not in mouse fibroblastic cell line NIH3T3. This element may be important in regulating the expression of neighbouring genes in a cell type specific manner. These results show that the MMTV LTR contains multiple regulatory elements necessary for the control of expression at its own promoter and the expression of neighbouring genes.

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Selected References

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  1. Angel P., Baumann I., Stein B., Delius H., Rahmsdorf H. J., Herrlich P. 12-O-tetradecanoyl-phorbol-13-acetate induction of the human collagenase gene is mediated by an inducible enhancer element located in the 5'-flanking region. Mol Cell Biol. 1987 Jun;7(6):2256–2266. doi: 10.1128/mcb.7.6.2256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baniahmad A., Muller M., Steiner C., Renkawitz R. Activity of two different silencer elements of the chicken lysozyme gene can be compensated by enhancer elements. EMBO J. 1987 Aug;6(8):2297–2303. doi: 10.1002/j.1460-2075.1987.tb02504.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bouvagnet P. F., Strehler E. E., White G. E., Strehler-Page M. A., Nadal-Ginard B., Mahdavi V. Multiple positive and negative 5' regulatory elements control the cell-type-specific expression of the embryonic skeletal myosin heavy-chain gene. Mol Cell Biol. 1987 Dec;7(12):4377–4389. doi: 10.1128/mcb.7.12.4377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brent R. Repression of transcription in yeast. Cell. 1985 Aug;42(1):3–4. doi: 10.1016/s0092-8674(85)80091-x. [DOI] [PubMed] [Google Scholar]
  5. Cato A. C., Henderson D., Ponta H. The hormone response element of the mouse mammary tumour virus DNA mediates the progestin and androgen induction of transcription in the proviral long terminal repeat region. EMBO J. 1987 Feb;6(2):363–368. doi: 10.1002/j.1460-2075.1987.tb04763.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cato A. C., Miksicek R., Schütz G., Arnemann J., Beato M. The hormone regulatory element of mouse mammary tumour virus mediates progesterone induction. EMBO J. 1986 Sep;5(9):2237–2240. doi: 10.1002/j.1460-2075.1986.tb04490.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cato A. C., Mink S., Nierlich B., Ponta H., Schaap D., Schuuring E., Sonnenberg A. Transforming growth factor-beta represses transcription of the mouse mammary tumour virus DNA in cultured mouse mammary cells. Oncogene. 1990 Jan;5(1):103–110. [PubMed] [Google Scholar]
  8. 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]
  9. Cato A. C., Weinmann J. Mineralocorticoid regulation of transcription of transfected mouse mammary tumor virus DNA in cultured kidney cells. J Cell Biol. 1988 Jun;106(6):2119–2125. doi: 10.1083/jcb.106.6.2119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Colantuoni V., Pirozzi A., Blance C., Cortese R. Negative control of liver-specific gene expression: cloned human retinol-binding protein gene is repressed in HeLa cells. EMBO J. 1987 Mar;6(3):631–636. doi: 10.1002/j.1460-2075.1987.tb04801.x. [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. Gallahan D., Callahan R. Mammary tumorigenesis in feral mice: identification of a new int locus in mouse mammary tumor virus (Czech II)-induced mammary tumors. J Virol. 1987 Jan;61(1):66–74. doi: 10.1128/jvi.61.1.66-74.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gorman C. M., Merlino G. T., Willingham M. C., Pastan I., Howard B. H. The Rous sarcoma virus long terminal repeat is a strong promoter when introduced into a variety of eukaryotic cells by DNA-mediated transfection. Proc Natl Acad Sci U S A. 1982 Nov;79(22):6777–6781. doi: 10.1073/pnas.79.22.6777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gorman C. M., Rigby P. W., Lane D. P. Negative regulation of viral enhancers in undifferentiated embryonic stem cells. Cell. 1985 Sep;42(2):519–526. doi: 10.1016/0092-8674(85)90109-6. [DOI] [PubMed] [Google Scholar]
  16. Herbomel P., Bourachot B., Yaniv M. Two distinct enhancers with different cell specificities coexist in the regulatory region of polyoma. Cell. 1984 Dec;39(3 Pt 2):653–662. doi: 10.1016/0092-8674(84)90472-0. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Hynes N. E., Groner B., Michalides R. Mouse mammary tumor virus: transcriptional control and involvement in tumorigenesis. Adv Cancer Res. 1984;41:155–184. doi: 10.1016/s0065-230x(08)60016-0. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Klein-Hitpass L., Ryffel G. U., Heitlinger E., Cato A. C. A 13 bp palindrome is a functional estrogen responsive element and interacts specifically with estrogen receptor. Nucleic Acids Res. 1988 Jan 25;16(2):647–663. doi: 10.1093/nar/16.2.647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. 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]
  23. Muglia L., Rothman-Denes L. B. Cell type-specific negative regulatory element in the control region of the rat alpha-fetoprotein gene. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7653–7657. doi: 10.1073/pnas.83.20.7653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nir U., Walker M. D., Rutter W. J. Regulation of rat insulin 1 gene expression: evidence for negative regulation in nonpancreatic cells. Proc Natl Acad Sci U S A. 1986 May;83(10):3180–3184. doi: 10.1073/pnas.83.10.3180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nusse R., Varmus H. E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell. 1982 Nov;31(1):99–109. doi: 10.1016/0092-8674(82)90409-3. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Ott M. O., Sperling L., Herbomel P., Yaniv M., Weiss M. C. Tissue-specific expression is conferred by a sequence from the 5' end of the rat albumin gene. EMBO J. 1984 Nov;3(11):2505–2510. doi: 10.1002/j.1460-2075.1984.tb02164.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Owens R. B., Smith H. S., Hackett A. J. Epithelial cell cultures from normal glandular tissue of mice. J Natl Cancer Inst. 1974 Jul;53(1):261–269. doi: 10.1093/jnci/53.1.261. [DOI] [PubMed] [Google Scholar]
  29. Peters G., Lee A. E., Dickson C. Concerted activation of two potential proto-oncogenes in carcinomas induced by mouse mammary tumour virus. Nature. 1986 Apr 17;320(6063):628–631. doi: 10.1038/320628a0. [DOI] [PubMed] [Google Scholar]
  30. Petit C., Levilliers J., Ott M. O., Weiss M. C. Tissue-specific expression of the rat albumin gene: genetic control of its extinction in microcell hybrids. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2561–2565. doi: 10.1073/pnas.83.8.2561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. 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]
  32. Reznikoff W. S., Siegele D. A., Cowing D. W., Gross C. A. The regulation of transcription initiation in bacteria. Annu Rev Genet. 1985;19:355–387. doi: 10.1146/annurev.ge.19.120185.002035. [DOI] [PubMed] [Google Scholar]
  33. Ringold G., Lasfargues E. Y., Bishop J. M., Varmus H. E. Production of mouse mammary tumor virus by cultured cells in the absence and presence of hormones: assay by molecular hybridization. Virology. 1975 May;65(1):135–147. doi: 10.1016/0042-6822(75)90014-8. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. 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]
  36. 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]

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