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PMID: 2369902 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

Cyclosporin A suppresses the expression of the interleukin 2 gene by inhibiting the binding of lymphocyte-specific factors to the IL-2 enhancer.

The EMBO journal ·Vol. 9 ·No. 8 ·1990-08-00 ·Pages 2529-36

Randak C, Brabletz T, Hergenröther M, Sobotta I, Serfling E

Abstract

Cyclosporin A (CsA), a powerful immunosuppressive drug, inhibits the synthesis of lymphokines in T lymphocytes at the level of gene transcription. Using protein extracts from El4 lymphoma cells we show that the binding of lymphocyte-specific factors interacting with the two so-called purine boxes (Pu-boxes) of the interleukin 2 (IL-2) enhancer are missing in CsA-treated cells. The CsA-sensitive factors are newly synthesized upon induction. The most prominent factor consists of 45 kd polypeptides and contacts both Pu-boxes at the two central G residues within the identical core sequence AAGAGGAAAA. The CsA-mediated suppression of factor binding to the Pu-boxes correlates well with functional studies in which the inducible, T cell-restricted proto-enhancer activity of Pu-boxes was selectively repressed by CsA. These observations support the conclusion that the suppression of factor binding to the Pu-boxes by CsA impairs the activity of IL-2 and of further lymphokine genes, thereby inhibiting the synthesis of lymphokines in T lymphocytes.

MeSH Terms
Animals Base Sequence Concanavalin A/pharmacology Cycloheximide/pharmacology Cyclosporins/pharmacology DNA-Binding Proteins/antagonists & inhibitors,metabolism Dactinomycin/pharmacology Enhancer Elements, Genetic/drug effects Humans Interleukin-2/genetics Lymphokines/genetics Mice Molecular Sequence Data Plasmids Promoter Regions, Genetic/drug effects Protein Biosynthesis/drug effects Sequence Homology, Nucleic Acid Suppression, Genetic/drug effects T-Lymphocytes/drug effects,immunology Transcription, Genetic/drug effects
Chemicals
Cyclosporins DNA-Binding Proteins Interleukin-2 Lymphokines Concanavalin A Dactinomycin Cycloheximide
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Randak C
Institut für Virologie und Immunbiologie, Universität Würzburg, FRG.
Brabletz T
Hergenröther M
Sobotta I
Serfling E
References (43)
43 references, click to expand
  1. Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins.
    Nature. 1989 Feb 2;337(6206):476-8 PMID: 2492638
  2. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells.
    Mol Cell Biol. 1982 Sep;2(9):1044-51 PMID: 6960240
  3. Kappa B-specific DNA binding proteins: role in the regulation of human interleukin-2 gene expression.
    Science. 1989 Apr 28;244(4903):457-60 PMID: 2497518
  4. Ubiquitous and lymphocyte-specific factors are involved in the induction of the mouse interleukin 2 gene in T lymphocytes.
    EMBO J. 1989 Feb;8(2):465-73 PMID: 2542017
  5. Complexity of the primary genetic response to mitogenic activation of human T cells.
    Mol Cell Biol. 1989 Mar;9(3):1041-8 PMID: 2498643
  6. Transcription factors AP-3 and AP-2 interact with the SV40 enhancer in a mutually exclusive manner.
    EMBO J. 1989 May;8(5):1455-60 PMID: 2548845
  7. A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin.
    Nature. 1989 Oct 26;341(6244):755-7 PMID: 2477714
  8. A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase.
    Nature. 1989 Oct 26;341(6244):758-60 PMID: 2477715
  9. Interleukin-2-dependent autocrine proliferation in T-cell development.
    Nature. 1989 Nov 2;342(6245):82-5 PMID: 2812004
  10. Identification of multiple cis-elements and trans-acting factors involved in the induced expression of human IL-2 gene.
    Nucleic Acids Res. 1989 Nov 25;17(22):9173-84 PMID: 2555786
  11. High efficiency polyoma DNA transfection of chloroquine treated cells.
    Nucleic Acids Res. 1983 Mar 11;11(5):1295-308 PMID: 6298741
  12. Cyclosporin A inhibits T-cell growth factor gene expression at the level of mRNA transcription.
    Proc Natl Acad Sci U S A. 1984 Aug;81(16):5214-8 PMID: 6332315
  13. Induction of interleukin 2 messenger RNA inhibited by cyclosporin A.
    Science. 1984 Dec 21;226(4681):1439-41 PMID: 6334364
  14. Structure of the chromosomal gene for murine interleukin 3.
    Proc Natl Acad Sci U S A. 1985 Jan;82(2):316-20 PMID: 3918308
  15. A viral enhancer element specifically active in human haematopoietic cells.
    Nature. 1985 Jun 13-19;315(6020):597-600 PMID: 2989696
  16. Structure of the chromosomal gene for granulocyte-macrophage colony stimulating factor: comparison of the mouse and human genes.
    EMBO J. 1985 Oct;4(10):2561-8 PMID: 3876930
  17. Regulation of human interleukin-2 gene: functional DNA sequences in the 5' flanking region for the gene expression in activated T lymphocytes.
    Cell. 1986 Aug 1;46(3):401-5 PMID: 3015413
  18. Affinity purification of sequence-specific DNA binding proteins.
    Proc Natl Acad Sci U S A. 1986 Aug;83(16):5889-93 PMID: 3461465
  19. Multiple nuclear factors interact with the immunoglobulin enhancer sequences.
    Cell. 1986 Aug 29;46(5):705-16 PMID: 3091258
  20. Purification and biochemical characterization of the promoter-specific transcription factor, Sp1.
    Science. 1986 Oct 3;234(4772):47-52 PMID: 3529394
  21. A 275 basepair fragment at the 5' end of the interleukin 2 gene enhances expression from a heterologous promoter in response to signals from the T cell antigen receptor.
    J Exp Med. 1987 Feb 1;165(2):395-407 PMID: 3102668
  22. Structural analysis of the mouse chromosomal gene encoding interleukin 4 which expresses B cell, T cell and mast cell stimulating activities.
    Nucleic Acids Res. 1987 Jan 12;15(1):333-44 PMID: 3029676
  23. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor.
    Cell. 1987 Jun 19;49(6):729-39 PMID: 3034432
  24. CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements.
    Nucleic Acids Res. 1987 Jul 10;15(13):5490 PMID: 3037497
  25. Transcription factor AP-2 mediates induction by two different signal-transduction pathways: protein kinase C and cAMP.
    Cell. 1987 Oct 23;51(2):251-60 PMID: 2822255
  26. A purine-rich DNA sequence motif present in SV40 and lymphotropic papovavirus binds a lymphoid-specific factor and contributes to enhancer activity in lymphoid cells.
    Genes Dev. 1987 Nov;1(9):962-72 PMID: 2828177
  27. The 5' region of the human interleukin 4 gene: structure and potential regulatory elements.
    Nucleic Acids Res. 1988 Jan 25;16(2):772 PMID: 3257560
  28. Cyclosporine--mechanism of action.
    Transplant Proc. 1988 Apr;20(2 Suppl 2):301-9 PMID: 3284073
  29. The same inducible nuclear proteins regulates mitogen activation of both the interleukin-2 receptor-alpha gene and type 1 HIV.
    Cell. 1988 Jun 3;53(5):827-36 PMID: 2836068
  30. Interleukin-2: inception, impact, and implications.
    Science. 1988 May 27;240(4856):1169-76 PMID: 3131876
  31. Characterization of antigen receptor response elements within the interleukin-2 enhancer.
    Mol Cell Biol. 1988 Apr;8(4):1715-24 PMID: 3260003
  32. Identification of a putative regulator of early T cell activation genes.
    Science. 1988 Jul 8;241(4862):202-5 PMID: 3260404
  33. A comparison of cyclosporine binding by cyclophilin and calmodulin and the identification of a novel 45 KD cyclosporine-binding phosphoprotein in Jurkat cells.
    Transplantation. 1988 Aug;46(2 Suppl):35S-40S PMID: 3043797
  34. Nuclear factors interacting with the mitogen-responsive regulatory region of the interleukin-2 gene.
    J Biol Chem. 1988 Dec 15;263(35):18904-10 PMID: 2848811
  35. Contingent genetic regulatory events in T lymphocyte activation.
    Science. 1989 Jan 20;243(4889):355-61 PMID: 2783497
  36. Peptidyl-prolyl cis-trans isomerase is the cyclosporin A-binding protein cyclophilin.
    Nature. 1989 Feb 2;337(6206):473-5 PMID: 2644542
  37. Cyclosporine.
    N Engl J Med. 1989 Dec 21;321(25):1725-38 PMID: 2687689
  38. Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation.
    Science. 1989 Dec 22;246(4937):1617-20 PMID: 2595372
  39. A 65-kappaD subunit of active NF-kappaB is required for inhibition of NF-kappaB by I kappaB.
    Genes Dev. 1989 Nov;3(11):1689-98 PMID: 2691328
  40. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene.
    Cell. 1990 Apr 6;61(1):113-24 PMID: 2180582
  41. Involvement of a common transcription factor in the regulated expression of IL-2 and IL-2 receptor genes.
    Int Immunol. 1989;1(1):43-9 PMID: 2518655
  42. Sequencing end-labeled DNA with base-specific chemical cleavages.
    Methods Enzymol. 1980;65(1):499-560 PMID: 6246368
  43. Identification of a novel lymphoid specific octamer binding protein (OTF-2B) by proteolytic clipping bandshift assay (PCBA).
    EMBO J. 1988 Dec 20;7(13):4221-9 PMID: 3072196
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1990-08-00
Pages
2529-36
Language
English
Region
England
NLM ID
8208664
PMCID
PMC552283
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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