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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 May 24;91(11):4915–4919. doi: 10.1073/pnas.91.11.4915

LR1 regulates c-myc transcription in B-cell lymphomas.

A Brys 1, N Maizels 1
PMCID: PMC43900  PMID: 8197157

Abstract

LR1 is a 106-kDa sequence-specific DNA-binding protein first identified as a potential regulator of immunoglobulin class switch recombination in B lymphocytes. Here we report that LR1 binds to a site 310 nt upstream of the human c-myc P1 promoter. Mutation of this site decreases reporter gene expression 5.5-fold in the Burkitt lymphoma line Raji and 3.8-fold in the lymphoma line BJAB. These experiments show that LR1 can function as a transcription factor and identify it as a cell type-specific activator of c-myc expression. There are multiple matches to the LR1 recognition consensus at the immunoglobulin heavy-chain locus and at c-myc, which further suggests that LR1 may play a dual role, facilitating c-myc translocation as well as regulating c-myc transcription.

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Selected References

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  1. Ahn J. K., Gavin B. J., Kumar G., Ward D. C. Transcriptional analysis of minute virus of mice P4 promoter mutants. J Virol. 1989 Dec;63(12):5425–5439. doi: 10.1128/jvi.63.12.5425-5439.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barberis A., Widenhorn K., Vitelli L., Busslinger M. A novel B-cell lineage-specific transcription factor present at early but not late stages of differentiation. Genes Dev. 1990 May;4(5):849–859. doi: 10.1101/gad.4.5.849. [DOI] [PubMed] [Google Scholar]
  3. Cory S. Activation of cellular oncogenes in hemopoietic cells by chromosome translocation. Adv Cancer Res. 1986;47:189–234. doi: 10.1016/s0065-230x(08)60200-6. [DOI] [PubMed] [Google Scholar]
  4. Croce C. M., Nowell P. C. Molecular genetics of human B cell neoplasia. Adv Immunol. 1986;38:245–274. doi: 10.1016/s0065-2776(08)60008-5. [DOI] [PubMed] [Google Scholar]
  5. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dunnick W., Hertz G. Z., Scappino L., Gritzmacher C. DNA sequences at immunoglobulin switch region recombination sites. Nucleic Acids Res. 1993 Feb 11;21(3):365–372. doi: 10.1093/nar/21.3.365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Duyao M. P., Buckler A. J., Sonenshein G. E. Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4727–4731. doi: 10.1073/pnas.87.12.4727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Friedman D. I. Integration host factor: a protein for all reasons. Cell. 1988 Nov 18;55(4):545–554. doi: 10.1016/0092-8674(88)90213-9. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Haluska F. G., Tsujimoto Y., Croce C. M. Oncogene activation by chromosome translocation in human malignancy. Annu Rev Genet. 1987;21:321–345. doi: 10.1146/annurev.ge.21.120187.001541. [DOI] [PubMed] [Google Scholar]
  11. Hay N., Bishop J. M., Levens D. Regulatory elements that modulate expression of human c-myc. Genes Dev. 1987 Sep;1(7):659–671. doi: 10.1101/gad.1.7.659. [DOI] [PubMed] [Google Scholar]
  12. Hay N., Takimoto M., Bishop J. M. A FOS protein is present in a complex that binds a negative regulator of MYC. Genes Dev. 1989 Mar;3(3):293–303. doi: 10.1101/gad.3.3.293. [DOI] [PubMed] [Google Scholar]
  13. Joos S., Falk M. H., Lichter P., Haluska F. G., Henglein B., Lenoir G. M., Bornkamm G. W. Variable breakpoints in Burkitt lymphoma cells with chromosomal t(8;14) translocation separate c-myc and the IgH locus up to several hundred kb. Hum Mol Genet. 1992 Nov;1(8):625–632. doi: 10.1093/hmg/1.8.625. [DOI] [PubMed] [Google Scholar]
  14. Kakkis E., Calame K. A plasmacytoma-specific factor binds the c-myc promoter region. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7031–7035. doi: 10.1073/pnas.84.20.7031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kakkis E., Riggs K. J., Gillespie W., Calame K. A transcriptional repressor of c-myc. Nature. 1989 Jun 29;339(6227):718–721. doi: 10.1038/339718a0. [DOI] [PubMed] [Google Scholar]
  16. Kelly K., Siebenlist U. The regulation and expression of c-myc in normal and malignant cells. Annu Rev Immunol. 1986;4:317–338. doi: 10.1146/annurev.iy.04.040186.001533. [DOI] [PubMed] [Google Scholar]
  17. Lenardo M., Pierce J. W., Baltimore D. Protein-binding sites in Ig gene enhancers determine transcriptional activity and inducibility. Science. 1987 Jun 19;236(4808):1573–1577. doi: 10.1126/science.3109035. [DOI] [PubMed] [Google Scholar]
  18. Magrath I. The pathogenesis of Burkitt's lymphoma. Adv Cancer Res. 1990;55:133–270. doi: 10.1016/s0065-230x(08)60470-4. [DOI] [PubMed] [Google Scholar]
  19. Pascal E., Tjian R. Different activation domains of Sp1 govern formation of multimers and mediate transcriptional synergism. Genes Dev. 1991 Sep;5(9):1646–1656. doi: 10.1101/gad.5.9.1646. [DOI] [PubMed] [Google Scholar]
  20. Pelicci P. G., Knowles D. M., 2nd, Magrath I., Dalla-Favera R. Chromosomal breakpoints and structural alterations of the c-myc locus differ in endemic and sporadic forms of Burkitt lymphoma. Proc Natl Acad Sci U S A. 1986 May;83(9):2984–2988. doi: 10.1073/pnas.83.9.2984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Postel E. H., Mango S. E., Flint S. J. A nuclease-hypersensitive element of the human c-myc promoter interacts with a transcription initiation factor. Mol Cell Biol. 1989 Nov;9(11):5123–5133. doi: 10.1128/mcb.9.11.5123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Richman A., Hayday A. Normal expression of a rearranged and mutated c-myc oncogene after transfection into fibroblasts. Science. 1989 Oct 27;246(4929):494–497. doi: 10.1126/science.2683072. [DOI] [PubMed] [Google Scholar]
  23. Riggs K. J., Merrell K. T., Wilson G., Calame K. Common factor 1 is a transcriptional activator which binds in the c-myc promoter, the skeletal alpha-actin promoter, and the immunoglobulin heavy-chain enhancer. Mol Cell Biol. 1991 Mar;11(3):1765–1769. doi: 10.1128/mcb.11.3.1765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Salvo J. J., Grindley N. D. The gamma delta resolvase bends the res site into a recombinogenic complex. EMBO J. 1988 Nov;7(11):3609–3616. doi: 10.1002/j.1460-2075.1988.tb03239.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Spandidos D. A., Zoumpourlis V., Lang J. C. Cis-platin responsive sequences in the human c-myc promoter. Anticancer Res. 1991 May-Jun;11(3):1339–1342. [PubMed] [Google Scholar]
  26. Spencer C. A., Groudine M. Control of c-myc regulation in normal and neoplastic cells. Adv Cancer Res. 1991;56:1–48. doi: 10.1016/s0065-230x(08)60476-5. [DOI] [PubMed] [Google Scholar]
  27. Spencer C. A., LeStrange R. C., Novak U., Hayward W. S., Groudine M. The block to transcription elongation is promoter dependent in normal and Burkitt's lymphoma c-myc alleles. Genes Dev. 1990 Jan;4(1):75–88. doi: 10.1101/gad.4.1.75. [DOI] [PubMed] [Google Scholar]
  28. Takimoto M., Quinn J. P., Farina A. R., Staudt L. M., Levens D. fos/jun and octamer-binding protein interact with a common site in a negative element of the human c-myc gene. J Biol Chem. 1989 May 25;264(15):8992–8999. [PubMed] [Google Scholar]
  29. Thalmeier K., Synovzik H., Mertz R., Winnacker E. L., Lipp M. Nuclear factor E2F mediates basic transcription and trans-activation by E1a of the human MYC promoter. Genes Dev. 1989 Apr;3(4):527–536. doi: 10.1101/gad.3.4.527. [DOI] [PubMed] [Google Scholar]
  30. Waldmann T. A. The arrangement of immunoglobulin and T cell receptor genes in human lymphoproliferative disorders. Adv Immunol. 1987;40:247–321. doi: 10.1016/s0065-2776(08)60241-2. [DOI] [PubMed] [Google Scholar]
  31. Williams M., Brys A., Weiner A. M., Maizels N. A rapid method for determining the molecular weight of a protein bound to nucleic acid in a mobility shift assay. Nucleic Acids Res. 1992 Sep 25;20(18):4935–4936. doi: 10.1093/nar/20.18.4935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Williams M., Hanakahi L. A., Maizels N. Purification and properties of LR1, an inducible DNA binding protein from mammalian B lymphocytes. J Biol Chem. 1993 Jun 25;268(18):13731–13737. [PubMed] [Google Scholar]
  33. Williams M., Maizels N. LR1, a lipopolysaccharide-responsive factor with binding sites in the immunoglobulin switch regions and heavy-chain enhancer. Genes Dev. 1991 Dec;5(12A):2353–2361. doi: 10.1101/gad.5.12a.2353. [DOI] [PubMed] [Google Scholar]

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