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PMID: 1702384 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The actions of cyclosporin A and FK506 suggest a novel step in the activation of T lymphocytes.

The EMBO journal ·Vol. 9 ·No. 13 ·1990-12-00 ·Pages 4425-33

Mattila PS, Ullman KS, Fiering S, Emmel EA, McCutcheon M, Crabtree GR, Herzenberg LA

Abstract

Cyclosporin A and FK506 are immunosuppressive compounds that have similar inhibitory effects on the expression of several lymphokines produced by T lymphocytes. Despite their similar effects the drugs bind to two different cytosolic protein, cyclophilin and FKBP respectively, which raises the possibility that they have different modes of action. Using constructs in which mRNA production controlled by a specific transcription factor could be readily measured we found that both cyclosporin A and FK506 completely inhibited transcription activated by NF-AT, NFIL2 A, NFIL2 B and partially inhibited transcription activated by NF kappa B. Cyclosporin A and FK506 inhibited only transcriptional activation that was dependent on Ca2+ mobilization. However, cyclosporin A and FK506 did not inhibit Ca2+ mobilization dependent expression of c-fos mRNA indicating that only a subset of signalling pathways regulated by Ca2+ is sensitive to these drugs. Furthermore, we did not observe any qualitative differences between the effect of cyclosporin A and FK506 on six different transcription factors which suggests that these drugs may interfere with the activity of a novel Ca2+ dependent step that regulates several transcription factors.

MeSH Terms
Anti-Bacterial Agents/pharmacology Base Sequence Calcium/pharmacology Cell Line Chromosome Mapping Cyclosporins/pharmacology Humans Immunosuppressive Agents/pharmacology Interleukin-1/genetics Lymphocyte Activation/drug effects Molecular Sequence Data Proto-Oncogene Proteins/genetics Proto-Oncogene Proteins c-fos RNA, Messenger/metabolism Signal Transduction/drug effects T-Lymphocytes/drug effects,metabolism Tacrolimus Transcription Factors/metabolism
Chemicals
Anti-Bacterial Agents Cyclosporins Immunosuppressive Agents Interleukin-1 Proto-Oncogene Proteins Proto-Oncogene Proteins c-fos RNA, Messenger Transcription Factors Calcium Tacrolimus
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Mattila P S
Department of Genetics, Stanford University School of Medicine, CA 94305.
Ullman K S
Fiering S
Emmel E A
McCutcheon M
Crabtree G R
Herzenberg L A
References (48)
48 references, click to expand
  1. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter.
    Nucleic Acids Res. 1984 Sep 25;12(18):7035-56 PMID: 6091052
  2. Identification of a putative regulator of early T cell activation genes.
    Science. 1988 Jul 8;241(4862):202-5 PMID: 3260404
  3. Induction of interleukin 2 messenger RNA inhibited by cyclosporin A.
    Science. 1984 Dec 21;226(4681):1439-41 PMID: 6334364
  4. Differential regulation of colony-stimulating factors and interleukin 2 production by cyclosporin A.
    Proc Natl Acad Sci U S A. 1987 May;84(10):3274-7 PMID: 3494996
  5. Hypothesis about the function of membrane-buried proline residues in transport proteins.
    Proc Natl Acad Sci U S A. 1986 Feb;83(4):917-21 PMID: 3456574
  6. Activation of a human T cell line: a two-stimulus requirement in the pretranslational events involved in the coordinate expression of interleukin 2 and gamma-interferon genes.
    J Immunol. 1985 Mar;134(3):1599-603 PMID: 3918105
  7. Complementary DNA encoding the human T-cell FK506-binding protein, a peptidylprolyl cis-trans isomerase distinct from cyclophilin.
    Proc Natl Acad Sci U S A. 1990 Jul;87(14):5440-3 PMID: 1695378
  8. The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells.
    J Immunol. 1990 Feb 15;144(4):1418-24 PMID: 1689353
  9. Molecular cloning and overexpression of the human FK506-binding protein FKBP.
    Nature. 1990 Aug 16;346(6285):671-4 PMID: 1696686
  10. T cell antigen receptor-mediated activation of phospholipase C requires tyrosine phosphorylation.
    Science. 1990 Mar 30;247(4950):1584-7 PMID: 2138816
  11. Inducible nuclear factor binding to the kappa B elements of the human immunodeficiency virus enhancer in T cells can be blocked by cyclosporin A in a signal-dependent manner.
    J Virol. 1990 Aug;64(8):4037-41 PMID: 2196387
  12. Infection of eucaryotic cells by helper-independent recombinant adenoviruses: early region 1 is not obligatory for integration of viral DNA.
    J Virol. 1984 May;50(2):606-14 PMID: 6323759
  13. A gel electrophoresis method for quantifying the binding of proteins to specific DNA regions: application to components of the Escherichia coli lactose operon regulatory system.
    Nucleic Acids Res. 1981 Jul 10;9(13):3047-60 PMID: 6269071
  14. New versatile plasmid vectors for expression of hybrid proteins coded by a cloned gene fused to lacZ gene sequences encoding an enzymatically active carboxy-terminal portion of beta-galactosidase.
    Gene. 1983 Nov;25(1):71-82 PMID: 6319233
  15. Equilibria and kinetics of lac repressor-operator interactions by polyacrylamide gel electrophoresis.
    Nucleic Acids Res. 1981 Dec 11;9(23):6505-25 PMID: 6275366
  16. Role of T3 surface molecules in human T-cell activation: T3-dependent activation results in an increase in cytoplasmic free calcium.
    Proc Natl Acad Sci U S A. 1984 Jul;81(13):4169-73 PMID: 6234599
  17. Conformation states of concanavalin A: kinetics of transitions induced by interaction with Mn2+ and Ca2+ ions.
    Biochemistry. 1977 Aug 23;16(17):3883-96 PMID: 20132
  18. The nature of the slow metal ion-dependent conformational transition in bovine prothrombin.
    Biochem J. 1979 Dec 1;183(3):513-7 PMID: 540028
  19. 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;72:248-54 PMID: 942051
  20. Sensitivity to cyclosporin A is mediated by cyclophilin in Neurospora crassa and Saccharomyces cerevisiae.
    Nature. 1989 Dec 21-28;342(6252):953-5 PMID: 2531848
  21. A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase.
    Nature. 1989 Oct 26;341(6244):758-60 PMID: 2477715
  22. 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
  23. The molecular heterogeneity of protein kinase C and its implications for cellular regulation.
    Nature. 1988 Aug 25;334(6184):661-5 PMID: 3045562
  24. Catalysis of proline isomerization during protein-folding reactions.
    Biochim Biophys Acta. 1988 Oct 12;956(3):256-66 PMID: 3048413
  25. The ninaA gene required for visual transduction in Drosophila encodes a homologue of cyclosporin A-binding protein.
    Nature. 1989 Mar 2;338(6210):67-70 PMID: 2493138
  26. Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins.
    Nature. 1989 Feb 2;337(6206):476-8 PMID: 2492638
  27. Peptidyl-prolyl cis-trans isomerase is the cyclosporin A-binding protein cyclophilin.
    Nature. 1989 Feb 2;337(6206):473-5 PMID: 2644542
  28. Drosophila ninaA gene encodes an eye-specific cyclophilin (cyclosporine A binding protein).
    Proc Natl Acad Sci U S A. 1989 Jul;86(14):5390-4 PMID: 2664782
  29. Complementary DNA for human T-cell cyclophilin.
    EMBO J. 1987 Apr;6(4):947-50 PMID: 3297675
  30. Catalysis of protein folding by prolyl isomerase.
    Nature. 1987 Sep 17-23;329(6136):268-70 PMID: 3306408
  31. HTLV-1 transactivator induces interleukin-2 receptor expression through an NF-kappa B-like factor.
    Nature. 1988 Jun 23;333(6175):776-8 PMID: 2838755
  32. Sequential expression of protooncogenes during lectin-stimulated mitogenesis of normal human lymphocytes.
    Proc Natl Acad Sci U S A. 1986 Jun;83(11):3982-6 PMID: 3012540
  33. Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements.
    Cell. 1987 Jun 19;49(6):741-52 PMID: 3034433
  34. A vector that replicates as a plasmid and can be efficiently selected in B-lymphoblasts transformed by Epstein-Barr virus.
    Mol Cell Biol. 1985 Feb;5(2):410-3 PMID: 2983194
  35. Fluorescence-activated cell analysis and sorting of viable mammalian cells based on beta-D-galactosidase activity after transduction of Escherichia coli lacZ.
    Proc Natl Acad Sci U S A. 1988 Apr;85(8):2603-7 PMID: 3128790
  36. Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-kappa B transcription factor.
    Cell. 1988 Apr 22;53(2):211-7 PMID: 3129195
  37. Single cell assay of a transcription factor reveals a threshold in transcription activated by signals emanating from the T-cell antigen receptor.
    Genes Dev. 1990 Oct;4(10):1823-34 PMID: 2123468
  38. c-Jun dimerizes with itself and with c-Fos, forming complexes of different DNA binding affinities.
    Cell. 1988 Dec 2;55(5):917-24 PMID: 3142692
  39. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism.
    Cell. 1986 Dec 26;47(6):921-8 PMID: 3096580
  40. The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes.
    J Immunol. 1989 Jul 15;143(2):718-26 PMID: 2472451
  41. Novel immunosuppressive agent, FK506. In vitro effects on the cloned T cell activation.
    J Immunol. 1987 Sep 15;139(6):1797-803 PMID: 2442255
  42. Effect of protein synthesis inhibitors on growth factor activation of c-fos, c-myc, and actin gene transcription.
    Mol Cell Biol. 1986 Apr;6(4):1050-7 PMID: 2431274
  43. 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
  44. Complete nucleotide sequence of the chromosomal gene for human IL-4 and its expression.
    J Immunol. 1989 Jan 1;142(1):274-82 PMID: 2535858
  45. Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation.
    Science. 1989 Dec 22;246(4937):1617-20 PMID: 2595372
  46. Contingent genetic regulatory events in T lymphocyte activation.
    Science. 1989 Jan 20;243(4889):355-61 PMID: 2783497
  47. Characterization of antigen receptor response elements within the interleukin-2 enhancer.
    Mol Cell Biol. 1988 Apr;8(4):1715-24 PMID: 3260003
  48. Cyclophilin: a specific cytosolic binding protein for cyclosporin A.
    Science. 1984 Nov 2;226(4674):544-7 PMID: 6238408
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1990-12-00
Pages
4425-33
Language
English
Region
England
NLM ID
8208664
PMCID
PMC552235
Subset
IM
Grants
NCI NIH HHS · CA39612 · United States
NCI NIH HHS · CA42509 · United States
NHLBI NIH HHS · HL 33942 · United States
External Links
PubMed source PMC Full Text View journal details
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