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. 1991 Feb 1;173(2):383–393. doi: 10.1084/jem.173.2.383

Developmental regulation of lck gene expression in T lymphocytes

PMCID: PMC2118802  PMID: 1988541

Abstract

In the mouse and human, mRNA transcripts encoding the lymphocyte- specific protein tyrosine kinase p56lck are derived from two separate promoters resulting in heterogeneity in the 5' untranslated region sequence. The proximal promoter lies just 5' to the coding region for the gene and is active only in thymocytes. In contrast, the distal promoter lies 34 kilobases (kb) 5' in the human, and is active both in thymocytes and mature peripheral T cells. As previously reported, transgenic mice bearing functional proximal promoter sequence juxtaposed with the SV40 large T antigen gene invariably develop lymphoid tumors confined to the thymus. In the current work, transgenic mice bearing a 2.6-kb fragment of the human distal promoter fused to the SV40 large T antigen gene express large T antigen in thymocytes and in peripheral lymphoid cells, and develop tumors of both the thymus and the peripheral lymphoid organs. The ability of the human distal promoter to function appropriately in transgenic mice is consistent with the strong similarity observed between the mouse and human distal promoter sequences. With the exception of a single short interval that serves as a target for binding of nuclear factors, significant sequence similarity is not seen when the distal and proximal promoter sequences are compared. Hence, developmentally regulated, lineage-specific transcription of the lck gene is mediated by distinct promoter sequences that appear to be capable of functioning independently.

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Selected References

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

  1. Adler H. T., Reynolds P. J., Kelley C. M., Sefton B. M. Transcriptional activation of lck by retrovirus promoter insertion between two lymphoid-specific promoters. J Virol. 1988 Nov;62(11):4113–4122. doi: 10.1128/jvi.62.11.4113-4122.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baldwin A. S., Jr, Sharp P. A. Binding of a nuclear factor to a regulatory sequence in the promoter of the mouse H-2Kb class I major histocompatibility gene. Mol Cell Biol. 1987 Jan;7(1):305–313. doi: 10.1128/mcb.7.1.305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baniahmad A., Steiner C., Köhne A. C., Renkawitz R. Modular structure of a chicken lysozyme silencer: involvement of an unusual thyroid hormone receptor binding site. Cell. 1990 May 4;61(3):505–514. doi: 10.1016/0092-8674(90)90532-j. [DOI] [PubMed] [Google Scholar]
  4. Buskin J. N., Hauschka S. D. Identification of a myocyte nuclear factor that binds to the muscle-specific enhancer of the mouse muscle creatine kinase gene. Mol Cell Biol. 1989 Jun;9(6):2627–2640. doi: 10.1128/mcb.9.6.2627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  6. Colbert M. C., Ciejek-Baez E. Alternative promoter usage by aldolase A during in vitro myogenesis. Dev Biol. 1988 Nov;130(1):392–396. doi: 10.1016/0012-1606(88)90444-7. [DOI] [PubMed] [Google Scholar]
  7. Corbin V., Maniatis T. Role of transcriptional interference in the Drosophila melanogaster Adh promoter switch. Nature. 1989 Jan 19;337(6204):279–282. doi: 10.1038/337279a0. [DOI] [PubMed] [Google Scholar]
  8. Garvin A. M., Abraham K. M., Forbush K. A., Farr A. G., Davison B. L., Perlmutter R. M. Disruption of thymocyte development and lymphomagenesis induced by SV40 T-antigen. Int Immunol. 1990;2(2):173–180. doi: 10.1093/intimm/2.2.173. [DOI] [PubMed] [Google Scholar]
  9. Garvin A. M., Pawar S., Marth J. D., Perlmutter R. M. Structure of the murine lck gene and its rearrangement in a murine lymphoma cell line. Mol Cell Biol. 1988 Aug;8(8):3058–3064. doi: 10.1128/mcb.8.8.3058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Goebl M. K. The PU.1 transcription factor is the product of the putative oncogene Spi-1. Cell. 1990 Jun 29;61(7):1165–1166. doi: 10.1016/0092-8674(90)90676-6. [DOI] [PubMed] [Google Scholar]
  11. Jones N. C., Rigby P. W., Ziff E. B. Trans-acting protein factors and the regulation of eukaryotic transcription: lessons from studies on DNA tumor viruses. Genes Dev. 1988 Mar;2(3):267–281. doi: 10.1101/gad.2.3.267. [DOI] [PubMed] [Google Scholar]
  12. Klemsz M. J., McKercher S. R., Celada A., Van Beveren C., Maki R. A. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell. 1990 Apr 6;61(1):113–124. doi: 10.1016/0092-8674(90)90219-5. [DOI] [PubMed] [Google Scholar]
  13. Koga Y., Kimura N., Minowada J., Mak T. W. Expression of the human T-cell-specific tyrosine kinase YT16 (lck) message in leukemic T-cell lines. Cancer Res. 1988 Feb 15;48(4):856–859. [PubMed] [Google Scholar]
  14. Lewis D. B., Larsen A., Wilson C. B. Reduced interferon-gamma mRNA levels in human neonates. Evidence for an intrinsic T cell deficiency independent of other genes involved in T cell activation. J Exp Med. 1986 Apr 1;163(4):1018–1023. doi: 10.1084/jem.163.4.1018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lewis D. B., Prickett K. S., Larsen A., Grabstein K., Weaver M., Wilson C. B. Restricted production of interleukin 4 by activated human T cells. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9743–9747. doi: 10.1073/pnas.85.24.9743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Littman D. R., Gettner S. N. Unusual intron in the immunoglobulin domain of the newly isolated murine CD4 (L3T4) gene. 1987 Jan 29-Feb 4Nature. 325(6103):453–455. doi: 10.1038/325453a0. [DOI] [PubMed] [Google Scholar]
  17. Marth J. D., Lewis D. B., Cooke M. P., Mellins E. D., Gearn M. E., Samelson L. E., Wilson C. B., Miller A. D., Perlmutter R. M. Lymphocyte activation provokes modification of a lymphocyte-specific protein tyrosine kinase (p56lck). J Immunol. 1989 Apr 1;142(7):2430–2437. [PubMed] [Google Scholar]
  18. Marth J. D., Lewis D. B., Wilson C. B., Gearn M. E., Krebs E. G., Perlmutter R. M. Regulation of pp56lck during T-cell activation: functional implications for the src-like protein tyrosine kinases. EMBO J. 1987 Sep;6(9):2727–2734. doi: 10.1002/j.1460-2075.1987.tb02566.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Marth J. D., Overell R. W., Meier K. E., Krebs E. G., Perlmutter R. M. Translational activation of the lck proto-oncogene. Nature. 1988 Mar 10;332(6160):171–173. doi: 10.1038/332171a0. [DOI] [PubMed] [Google Scholar]
  20. Marth J. D., Peet R., Krebs E. G., Perlmutter R. M. A lymphocyte-specific protein-tyrosine kinase gene is rearranged and overexpressed in the murine T cell lymphoma LSTRA. Cell. 1985 Dec;43(2 Pt 1):393–404. doi: 10.1016/0092-8674(85)90169-2. [DOI] [PubMed] [Google Scholar]
  21. Perlmutter R. M., Berson B., Griffin J. A., Hood L. Diversity in the germline antibody repertoire. Molecular evolution of the T15 VN gene family. J Exp Med. 1985 Dec 1;162(6):1998–2016. doi: 10.1084/jem.162.6.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Perlmutter R. M., Marth J. D., Lewis D. B., Peet R., Ziegler S. F., Wilson C. B. Structure and expression of lck transcripts in human lymphoid cells. J Cell Biochem. 1988 Oct;38(2):117–126. doi: 10.1002/jcb.240380206. [DOI] [PubMed] [Google Scholar]
  23. Perlmutter R. M., Marth J. D., Ziegler S. F., Garvin A. M., Pawar S., Cooke M. P., Abraham K. M. Specialized protein tyrosine kinase proto-oncogenes in hematopoietic cells. Biochim Biophys Acta. 1989 Feb;948(3):245–262. doi: 10.1016/0304-419x(89)90001-2. [DOI] [PubMed] [Google Scholar]
  24. Perlmutter R. M. T cell signaling. Science. 1989 Jul 28;245(4916):344–344. doi: 10.1126/science.2787933. [DOI] [PubMed] [Google Scholar]
  25. Reynolds P. J., Lesley J., Trotter J., Schulte R., Hyman R., Sefton B. M. Changes in the relative abundance of type I and type II lck mRNA transcripts suggest differential promoter usage during T-cell development. Mol Cell Biol. 1990 Aug;10(8):4266–4270. doi: 10.1128/mcb.10.8.4266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. Sartor O., Gregory F. S., Templeton N. S., Pawar S., Perlmutter R. M., Rosen N. Selective expression of alternative lck mRNAs in human malignant cell lines. Mol Cell Biol. 1989 Jul;9(7):2983–2988. doi: 10.1128/mcb.9.7.2983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schibler U., Hagenbüchle O., Wellauer P. K., Pittet A. C. Two promoters of different strengths control the transcription of the mouse alpha-amylase gene Amy-1a in the parotid gland and the liver. Cell. 1983 Jun;33(2):501–508. doi: 10.1016/0092-8674(83)90431-2. [DOI] [PubMed] [Google Scholar]
  29. Scollay R., Wilson A., D'Amico A., Kelly K., Egerton M., Pearse M., Wu L., Shortman K. Developmental status and reconstitution potential of subpopulations of murine thymocytes. Immunol Rev. 1988 Aug;104:81–120. doi: 10.1111/j.1600-065x.1988.tb00760.x. [DOI] [PubMed] [Google Scholar]
  30. Sturm R., Baumruker T., Franza B. R., Jr, Herr W. A 100-kD HeLa cell octamer binding protein (OBP100) interacts differently with two separate octamer-related sequences within the SV40 enhancer. Genes Dev. 1987 Dec;1(10):1147–1160. doi: 10.1101/gad.1.10.1147. [DOI] [PubMed] [Google Scholar]
  31. Takadera T., Leung S., Gernone A., Koga Y., Takihara Y., Miyamoto N. G., Mak T. W. Structure of the two promoters of the human lck gene: differential accumulation of two classes of lck transcripts in T cells. Mol Cell Biol. 1989 May;9(5):2173–2180. doi: 10.1128/mcb.9.5.2173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Turner J. M., Brodsky M. H., Irving B. A., Levin S. D., Perlmutter R. M., Littman D. R. Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell. 1990 Mar 9;60(5):755–765. doi: 10.1016/0092-8674(90)90090-2. [DOI] [PubMed] [Google Scholar]
  33. Veillette A., Bolen J. B., Bookman M. A. Alterations in tyrosine protein phosphorylation induced by antibody-mediated cross-linking of the CD4 receptor of T lymphocytes. Mol Cell Biol. 1989 Oct;9(10):4441–4446. doi: 10.1128/mcb.9.10.4441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Voronova A. F., Adler H. T., Sefton B. M. Two lck transcripts containing different 5' untranslated regions are present in T cells. Mol Cell Biol. 1987 Dec;7(12):4407–4413. doi: 10.1128/mcb.7.12.4407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Watanabe H., Wada T., Handa H. Transcription factor E4TF1 contains two subunits with different functions. EMBO J. 1990 Mar;9(3):841–847. doi: 10.1002/j.1460-2075.1990.tb08181.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wilson C. B., Westall J., Johnston L., Lewis D. B., Dower S. K., Alpert A. R. Decreased production of interferon-gamma by human neonatal cells. Intrinsic and regulatory deficiencies. J Clin Invest. 1986 Mar;77(3):860–867. doi: 10.1172/JCI112383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Woisetschlaeger M., Yandava C. N., Furmanski L. A., Strominger J. L., Speck S. H. Promoter switching in Epstein-Barr virus during the initial stages of infection of B lymphocytes. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1725–1729. doi: 10.1073/pnas.87.5.1725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. von Boehmer H. The developmental biology of T lymphocytes. Annu Rev Immunol. 1988;6:309–326. doi: 10.1146/annurev.iy.06.040188.001521. [DOI] [PubMed] [Google Scholar]

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