Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1992 Dec;66(12):7080–7088. doi: 10.1128/jvi.66.12.7080-7088.1992

Contributions to transcriptional activity and to viral leukemogenicity made by sequences within and downstream of the MCF13 murine leukemia virus enhancer.

J C Tupper 1, H Chen 1, E F Hays 1, G C Bristol 1, F K Yoshimura 1
PMCID: PMC240380  PMID: 1331510

Abstract

We have identified nucleotide sequences that regulate transcription in both a cell-type-specific and general manner in the long terminal repeat of the MCF13 murine leukemia virus. Besides the enhancer element, we have observed that the region between the enhancer and promoter (DEN) has a profound effect on transcription in different cell types. This effect, however, was dependent on the copy number of enhancer repeats and was detectable in the presence of a single repeat. When two enhancer repeats were present, the effect of DEN on transcription was abrogated except in T cells. DEN also makes a significant contribution to the leukemogenic property of the MCF13 retrovirus. Its deletion from the MCF13 virus dramatically reduced the incidence of thymic lymphoma and increased the latency of disease in comparison with the wild-type virus. This effect was most marked when one rather than two enhancer repeats was present in the mutant viruses. We also observed that the removal of one repeat alone remarkably reduced leukemogenicity by the MCF13 virus. A newly identified protein-binding site (MLPal) located within DEN affects transcription only in T cells, and its deletion attenuates the ability of an MCF13 virus with a single enhancer repeat to induce thymic lymphoma. This observation suggests that the MLPal protein-binding site contributes to the effect of the DEN region on T-cell-specific transcription and viral leukemogenicity. This study identifies the importance of nonenhancer sequences in the long terminal repeat for the oncogenesis of the MCF13 retrovirus.

Full text

PDF
7080

Selected References

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

  1. Boral A. L., Okenquist S. A., Lenz J. Identification of the SL3-3 virus enhancer core as a T-lymphoma cell-specific element. J Virol. 1989 Jan;63(1):76–84. doi: 10.1128/jvi.63.1.76-84.1989. [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: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  3. Chatis P. A., Holland C. A., Hartley J. W., Rowe W. P., Hopkins N. Role for the 3' end of the genome in determining disease specificity of Friend and Moloney murine leukemia viruses. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4408–4411. doi: 10.1073/pnas.80.14.4408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chatis P. A., Holland C. A., Silver J. E., Frederickson T. N., Hopkins N., Hartley J. W. A 3' end fragment encompassing the transcriptional enhancers of nondefective Friend virus confers erythroleukemogenicity on Moloney leukemia virus. J Virol. 1984 Oct;52(1):248–254. doi: 10.1128/jvi.52.1.248-254.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cloyd M. W., Hartley J. W., Rowe W. P. Lymphomagenicity of recombinant mink cell focus-inducing murine leukemia viruses. J Exp Med. 1980 Mar 1;151(3):542–552. doi: 10.1084/jem.151.3.542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Corcoran L. M., Adams J. M., Dunn A. R., Cory S. Murine T lymphomas in which the cellular myc oncogene has been activated by retroviral insertion. Cell. 1984 May;37(1):113–122. doi: 10.1016/0092-8674(84)90306-4. [DOI] [PubMed] [Google Scholar]
  7. Crabb D. W., Dixon J. E. A method for increasing the sensitivity of chloramphenicol acetyltransferase assays in extracts of transfected cultured cells. Anal Biochem. 1987 May 15;163(1):88–92. doi: 10.1016/0003-2697(87)90096-0. [DOI] [PubMed] [Google Scholar]
  8. Cuypers H. T., Selten G., Quint W., Zijlstra M., Maandag E. R., Boelens W., van Wezenbeek P., Melief C., Berns A. Murine leukemia virus-induced T-cell lymphomagenesis: integration of proviruses in a distinct chromosomal region. Cell. 1984 May;37(1):141–150. doi: 10.1016/0092-8674(84)90309-x. [DOI] [PubMed] [Google Scholar]
  9. Dai H. Y., Etzerodt M., Baekgaard A. J., Lovmand S., Jørgensen P., Kjeldgaard N. O., Pedersen F. S. Multiple sequence elements in the U3 region of the leukemogenic murine retrovirus SL3-2 contribute to cell-dependent gene expression. Virology. 1990 Apr;175(2):581–585. doi: 10.1016/0042-6822(90)90445-w. [DOI] [PubMed] [Google Scholar]
  10. DesGroseillers L., Jolicoeur P. Mapping the viral sequences conferring leukemogenicity and disease specificity in Moloney and amphotropic murine leukemia viruses. J Virol. 1984 Nov;52(2):448–456. doi: 10.1128/jvi.52.2.448-456.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Evans L. H., Morrison R. P., Malik F. G., Portis J., Britt W. J. A neutralizable epitope common to the envelope glycoproteins of ecotropic, polytropic, xenotropic, and amphotropic murine leukemia viruses. J Virol. 1990 Dec;64(12):6176–6183. doi: 10.1128/jvi.64.12.6176-6183.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Golemis E. A., Speck N. A., Hopkins N. Alignment of U3 region sequences of mammalian type C viruses: identification of highly conserved motifs and implications for enhancer design. J Virol. 1990 Feb;64(2):534–542. doi: 10.1128/jvi.64.2.534-542.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Golemis E., Li Y., Fredrickson T. N., Hartley J. W., Hopkins N. Distinct segments within the enhancer region collaborate to specify the type of leukemia induced by nondefective Friend and Moloney viruses. J Virol. 1989 Jan;63(1):328–337. doi: 10.1128/jvi.63.1.328-337.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Graves B. J., Eisenman R. N., McKnight S. L. Delineation of transcriptional control signals within the Moloney murine sarcoma virus long terminal repeat. Mol Cell Biol. 1985 Aug;5(8):1948–1958. doi: 10.1128/mcb.5.8.1948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gunther C. V., Nye J. A., Bryner R. S., Graves B. J. Sequence-specific DNA binding of the proto-oncoprotein ets-1 defines a transcriptional activator sequence within the long terminal repeat of the Moloney murine sarcoma virus. Genes Dev. 1990 Apr;4(4):667–679. doi: 10.1101/gad.4.4.667. [DOI] [PubMed] [Google Scholar]
  16. Hallberg B., Schmidt J., Luz A., Pedersen F. S., Grundström T. SL3-3 enhancer factor 1 transcriptional activators are required for tumor formation by SL3-3 murine leukemia virus. J Virol. 1991 Aug;65(8):4177–4181. doi: 10.1128/jvi.65.8.4177-4181.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hanecak R., Mittal S., Davis B. R., Fan H. Generation of infectious Moloney murine leukemia viruses with deletions in the U3 portion of the long terminal repeat. Mol Cell Biol. 1986 Dec;6(12):4634–4640. doi: 10.1128/mcb.6.12.4634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hanecak R., Pattengale P. K., Fan H. Deletion of a GC-rich region flanking the enhancer element within the long terminal repeat sequences alters the disease specificity of Moloney murine leukemia virus. J Virol. 1991 Oct;65(10):5357–5363. doi: 10.1128/jvi.65.10.5357-5363.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hartley J. W., Wolford N. K., Old L. J., Rowe W. P. A new class of murine leukemia virus associated with development of spontaneous lymphomas. Proc Natl Acad Sci U S A. 1977 Feb;74(2):789–792. doi: 10.1073/pnas.74.2.789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hayward W. S., Neel B. G., Astrin S. M. Activation of a cellular onc gene by promoter insertion in ALV-induced lymphoid leukosis. Nature. 1981 Apr 9;290(5806):475–480. doi: 10.1038/290475a0. [DOI] [PubMed] [Google Scholar]
  21. Ho I. C., Vorhees P., Marin N., Oakley B. K., Tsai S. F., Orkin S. H., Leiden J. M. Human GATA-3: a lineage-restricted transcription factor that regulates the expression of the T cell receptor alpha gene. EMBO J. 1991 May;10(5):1187–1192. doi: 10.1002/j.1460-2075.1991.tb08059.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hollon T., Yoshimura F. K. Mapping of functional regions of murine retrovirus long terminal repeat enhancers: enhancer domains interact and are not independent in their contributions to enhancer activity. J Virol. 1989 Aug;63(8):3353–3361. doi: 10.1128/jvi.63.8.3353-3361.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ishimoto A., Takimoto M., Adachi A., Kakuyama M., Kato S., Kakimi K., Fukuoka K., Ogiu T., Matsuyama M. Sequences responsible for erythroid and lymphoid leukemia in the long terminal repeats of Friend-mink cell focus-forming and Moloney murine leukemia viruses. J Virol. 1987 Jun;61(6):1861–1866. doi: 10.1128/jvi.61.6.1861-1866.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jolicoeur P., DesGroseillers L. Neurotropic Cas-BR-E murine leukemia virus harbors several determinants of leukemogenicity mapping in different regions of the genome. J Virol. 1985 Nov;56(2):639–643. doi: 10.1128/jvi.56.2.639-643.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ko L. J., Yamamoto M., Leonard M. W., George K. M., Ting P., Engel J. D. Murine and human T-lymphocyte GATA-3 factors mediate transcription through a cis-regulatory element within the human T-cell receptor delta gene enhancer. Mol Cell Biol. 1991 May;11(5):2778–2784. doi: 10.1128/mcb.11.5.2778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Laimins L. A., Gruss P., Pozzatti R., Khoury G. Characterization of enhancer elements in the long terminal repeat of Moloney murine sarcoma virus. J Virol. 1984 Jan;49(1):183–189. doi: 10.1128/jvi.49.1.183-189.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Li Y., Golemis E., Hartley J. W., Hopkins N. Disease specificity of nondefective Friend and Moloney murine leukemia viruses is controlled by a small number of nucleotides. J Virol. 1987 Mar;61(3):693–700. doi: 10.1128/jvi.61.3.693-700.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. LoSardo J. E., Boral A. L., Lenz J. Relative importance of elements within the SL3-3 virus enhancer for T-cell specificity. J Virol. 1990 Apr;64(4):1756–1763. doi: 10.1128/jvi.64.4.1756-1763.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. LoSardo J. E., Cupelli L. A., Short M. K., Berman J. W., Lenz J. Differences in activities of murine retroviral long terminal repeats in cytotoxic T lymphocytes and T-lymphoma cells. J Virol. 1989 Mar;63(3):1087–1094. doi: 10.1128/jvi.63.3.1087-1094.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lovmand S., Kjeldgaard N. O., Jørgensen P., Pedersen F. S. Enhancer functions in U3 of Akv virus: a role for cooperativity of a tandem repeat unit and its flanking DNA sequences. J Virol. 1990 Jul;64(7):3185–3191. doi: 10.1128/jvi.64.7.3185-3191.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Manley N. R., O'Connell M. A., Sharp P. A., Hopkins N. Nuclear factors that bind to the enhancer region of nondefective Friend murine leukemia virus. J Virol. 1989 Oct;63(10):4210–4223. doi: 10.1128/jvi.63.10.4210-4223.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Marine J., Winoto A. The human enhancer-binding protein Gata3 binds to several T-cell receptor regulatory elements. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7284–7288. doi: 10.1073/pnas.88.16.7284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. McGrath M. S., Pillemer E., Kooistra D., Weissman I. L. The role of MuLV receptors on T-lymphoma cells in lymphoma cell proliferation. Contemp Top Immunobiol. 1980;11:157–184. doi: 10.1007/978-1-4684-3701-0_5. [DOI] [PubMed] [Google Scholar]
  34. Nilsson P., Hallberg B., Thornell A., Grundström T. Mutant analysis of protein interactions with a nuclear factor I binding site in the SL3-3 virus enhancer. Nucleic Acids Res. 1989 Jun 12;17(11):4061–4075. doi: 10.1093/nar/17.11.4061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Nowinski R. C., Hays E. F. Oncogenicity of AKR endogenous leukemia viruses. J Virol. 1978 Jul;27(1):13–18. doi: 10.1128/jvi.27.1.13-18.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. 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]
  37. Payne G. S., Bishop J. M., Varmus H. E. Multiple arrangements of viral DNA and an activated host oncogene in bursal lymphomas. Nature. 1982 Jan 21;295(5846):209–214. doi: 10.1038/295209a0. [DOI] [PubMed] [Google Scholar]
  38. Pedersen F. S., Crowther R. L., Tenney D. Y., Reimold A. M., Haseltine W. A. Novel leukaemogenic retroviruses isolated from cell line derived from spontaneous AKR tumour. Nature. 1981 Jul 9;292(5819):167–170. doi: 10.1038/292167a0. [DOI] [PubMed] [Google Scholar]
  39. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sankar-Mistry P., Jolicoeur P. Frequent isolation of ecotropic murine leukemia virus after x-ray irradiation of C57BL/6 mice and establishment of producer lymphoid cell lines from radiation-induced lymphomas. J Virol. 1980 Jul;35(1):270–275. doi: 10.1128/jvi.35.1.270-275.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Sayers J. R., Schmidt W., Eckstein F. 5'-3' exonucleases in phosphorothioate-based oligonucleotide-directed mutagenesis. Nucleic Acids Res. 1988 Feb 11;16(3):791–802. doi: 10.1093/nar/16.3.791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sitbon M., Nishio J., Wehrly K., Lodmell D., Chesebro B. Use of a focal immunofluorescence assay on live cells for quantitation of retroviruses: distinction of host range classes in virus mixtures and biological cloning of dual-tropic murine leukemia viruses. Virology. 1985 Feb;141(1):110–118. doi: 10.1016/0042-6822(85)90187-4. [DOI] [PubMed] [Google Scholar]
  43. Sleigh M. J. A nonchromatographic assay for expression of the chloramphenicol acetyltransferase gene in eucaryotic cells. Anal Biochem. 1986 Jul;156(1):251–256. doi: 10.1016/0003-2697(86)90180-6. [DOI] [PubMed] [Google Scholar]
  44. Speck N. A., Baltimore D. Six distinct nuclear factors interact with the 75-base-pair repeat of the Moloney murine leukemia virus enhancer. Mol Cell Biol. 1987 Mar;7(3):1101–1110. doi: 10.1128/mcb.7.3.1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Speck N. A., Renjifo B., Golemis E., Fredrickson T. N., Hartley J. W., Hopkins N. Mutation of the core or adjacent LVb elements of the Moloney murine leukemia virus enhancer alters disease specificity. Genes Dev. 1990 Feb;4(2):233–242. doi: 10.1101/gad.4.2.233. [DOI] [PubMed] [Google Scholar]
  46. Speck N. A., Renjifo B., Hopkins N. Point mutations in the Moloney murine leukemia virus enhancer identify a lymphoid-specific viral core motif and 1,3-phorbol myristate acetate-inducible element. J Virol. 1990 Feb;64(2):543–550. doi: 10.1128/jvi.64.2.543-550.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Thornell A., Hallberg B., Grundström T. Binding of SL3-3 enhancer factor 1 transcriptional activators to viral and chromosomal enhancer sequences. J Virol. 1991 Jan;65(1):42–50. doi: 10.1128/jvi.65.1.42-50.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Thornell A., Hallberg B., Grundström T. Differential protein binding in lymphocytes to a sequence in the enhancer of the mouse retrovirus SL3-3. Mol Cell Biol. 1988 Apr;8(4):1625–1637. doi: 10.1128/mcb.8.4.1625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Vogt M., Haggblom C., Swift S., Haas M. Envelope gene and long terminal repeat determine the different biological properties of Rauscher, Friend, and Moloney mink cell focus-inducing viruses. J Virol. 1985 Jul;55(1):184–192. doi: 10.1128/jvi.55.1.184-192.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Vogt M. Properties of "mink cell focus-inducing" (MCF) virus isolated from spontaneous lymphoma lines of BALB/c mice carrying Moloney leukemia virus as an endogenous virus. Virology. 1979 Feb;93(1):226–236. doi: 10.1016/0042-6822(79)90290-3. [DOI] [PubMed] [Google Scholar]
  51. Wang S. W., Speck N. A. Purification of core-binding factor, a protein that binds the conserved core site in murine leukemia virus enhancers. Mol Cell Biol. 1992 Jan;12(1):89–102. doi: 10.1128/mcb.12.1.89. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Weiher H., König M., Gruss P. Multiple point mutations affecting the simian virus 40 enhancer. Science. 1983 Feb 11;219(4585):626–631. doi: 10.1126/science.6297005. [DOI] [PubMed] [Google Scholar]
  53. Yamamoto M., Ko L. J., Leonard M. W., Beug H., Orkin S. H., Engel J. D. Activity and tissue-specific expression of the transcription factor NF-E1 multigene family. Genes Dev. 1990 Oct;4(10):1650–1662. doi: 10.1101/gad.4.10.1650. [DOI] [PubMed] [Google Scholar]
  54. Yoshimura F. K., Davison B., Chaffin K. Murine leukemia virus long terminal repeat sequences can enhance gene activity in a cell-type-specific manner. Mol Cell Biol. 1985 Oct;5(10):2832–2835. doi: 10.1128/mcb.5.10.2832. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Yoshimura F. K. Identification of a DNA fragment from a molecularly cloned mink cell focus-inducing murine leukemia virus specific for xenotropic virus-related sequences. J Virol. 1982 Jul;43(1):348–351. doi: 10.1128/jvi.43.1.348-351.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Yoshimura F. K., Tupper J., Diem K. Differential DNA binding of nuclear proteins to a long terminal repeat region of the MCF13 and Akv murine leukemia viruses. J Virol. 1989 Nov;63(11):4945–4948. doi: 10.1128/jvi.63.11.4945-4948.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES