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Chemical Compound Review

AC1O52AA     30-ethyl-33-[(E)-1-hydroxy-2- methyl-hex-4...

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Disease relevance of cyclosporin A

  • In certain nonhuman primate cells, the CA-CypA interaction is essential for restriction: HIV-1 infectivity is increased >100-fold by cyclosporin A (CsA), a competitive inhibitor of the interaction, or by an HIV-1 CA mutation that disrupts CypA binding [1].
  • Furthermore, the fibrosis that occurs in the granuloma is apparently T cell--dependent, since no fibrotic lesions developed in SCW-injected athymic nude rats nor in SCW-injected animals treated with the T cell inhibitor, cyclosporin A (CsA) [2].
  • These data provide the first demonstration in vivo that activation of a protein phosphatase can inactivate I kappa B, and suggest one possible explanation for mechanism-based toxicities associated with FK-506 and CsA by demonstrating that these drugs can inhibit the calcineurin-dependent activation of a virtually ubiquitous transcription factor [3].
  • Cyclosporin A (CsA) prevents hypertrophy caused by activation of calcineurin [Molkentin, J. D., Lu, J.-R., Antos, C. L., Markham, B., Richardson, J., Robbins, J., Grant, S. R. & Olson, E. N. (1998) Cell 93, 215-228] [4].
  • CypA knock-down eliminated the HIV-1 stimulatory effect of cyclosporin A (CsA), a competitive inhibitor of the CypA-CA interaction, or of CA mutants that block binding to CypA but caused no change in titer of retroviruses that don't interact with CypA [5].

Psychiatry related information on cyclosporin A

  • Injection of CsA led to enhanced phosphorylation of tau at Ser-262 (12E8 site), Ser-198, Ser-199, and/or Ser-202 (Tau-1 site) and Ser-396 and/or Ser-404 (PHF-1 site), as well as to impaired spatial memory, which are two characteristic features of Alzheimer's disease [6].
  • Individual differences in the in vitro response to cyclosporin A (CsA): possible heterogeneity in the involvement of the CD28-B7/BB1 pathway [7].

High impact information on cyclosporin A

  • Treatment of Col6a1-/- mice with CsA rescued the muscle ultrastructural defects and markedly decreased the number of apoptotic nuclei in vivo [8].
  • A cyp C fusion protein has peptidyl-prolyl isomerase activity, and CsA inhibits this activity [9].
  • We report the cloning and characterization of a new binding protein for the immunosuppressive drug cyclosporin A (CsA) [9].
  • We propose that the p77 is involved in cyp C native function and that the p55 is involved in signal transduction events blocked by treatment with immunosuppressive levels of CsA [9].
  • In concordant models, this type of rejection is prevented by brief complement inhibition by cobra venom factor (CVF) and sustained T-cell immunosuppression by cyclosporin A (CyA) [10].

Chemical compound and disease context of cyclosporin A


Biological context of cyclosporin A

  • The immunosuppressive drugs cyclosporin A (CsA) and FK506 both interfere with a Ca(2+)-sensitive T-cell signal transduction pathway, thereby preventing the activation of specific transcription factors (such as NF-AT and NF-IL2A) involved in lymphokine gene expression [16].
  • Here we report that transfection of a calcineurin catalytic subunit increases the 50% inhibitory concentration (IC50) of the immunosuppressants FK-506 and CsA, and that a mutant subunit acts in synergy with phorbol ester alone to activate the interleukin-2 promoter in a drug-sensitive manner [17].
  • The first 38 amino-acid residues of porcine PPIase and of bovine cyclophilin are identical and the two proteins both have a relative molecular mass of about 17,000 (ref. 7). The catalysis of prolyl isomerization in oligopeptides and of protein folding by PPIase are strongly inhibited in the presence of low levels of CsA [18].
  • These results show that, like alpha/beta T cells, V gamma 3+ thymocytes differentiate from TCRlow precursors to cells with a mature phenotype and that CsA inhibits this transition [19].
  • In the absence of cyclosporin A (CsA), there was no difference in graft survival time between CX(3)CR1(-/-) and CX(3)CR1(+/+) recipient mice [20].

Anatomical context of cyclosporin A


Associations of cyclosporin A with other chemical compounds

  • Both Dex and CsA inhibited the binding of transcription factors AP-1 and NF-AT, but not of NF-kB and OCT-1/OAF, to their corresponding sites on the IL-2 gene promoter [23].
  • Flow cytometric analysis of rhodamine 123 dye efflux indicated a functional P-gp that was efficiently blocked by verapamil or cyclosporin A (CsA) [24].
  • Transactivation by recombinant NFAT1 in Jurkat T cells requires dual stimulation with ionomycin and phorbol 12-myristate 13-acetate; this activity is potentiated by coexpression of constitutively active calcineurin and is inhibited by CsA [25].
  • No apoptosis was detectable at 0.01 microgram/mL adriamycin, the in vivo steady-state level, with or without CsA [24].
  • We have investigated the potential involvement of the immune system in the pathogenesis of EMC-D-induced diabetes using cyclosporin-A (CyA), a potent immunosuppressive drug [26].

Gene context of cyclosporin A

  • CD40-mediated induction of bcl-x required neither wild-type BTK nor extracellular Ca2+ and was insensitive to CsA [27].
  • When expressed in Jurkat T cells, recombinant NFAT1 is regulated, as expected, by the calmodulin-dependent phosphatase calcineurin, and its function is inhibited by the immunosuppressive agent cyclosporin A (CsA) [25].
  • The suppressive effect on IFN-gamma production was also more potent than that of either DEX or CyA [28].
  • Cyclophilins comprise a highly conserved family of proteins which are the primary targets of the potent immunosuppressive drug, cyclosporin A (CsA), and which display peptidyl prolyl cis-trans-isomerase (PPIase) activity [29].
  • This up-regulation of Cdk4 mRNA and protein was resistant to the immunosuppressant drugs cyclosporin A (CsA) and FK506 [30].

Analytical, diagnostic and therapeutic context of cyclosporin A

  • Although NF-AT has not been cloned or purified, there is evidence that it is a major target for immunosuppression by cyclosporin A (CsA) and FK506 (refs 2-7) [31].
  • Affinity chromatography with FK506, CsA, and rapamycin matrices indicates that the same set of immunophilins present in RBL-2H3 cells have been found in Jurkat T cells and calf thymus; however, the relative amounts of these proteins differ in the two cell types [21].
  • Gel mobility shift assays indicated that the binding activities of the factors specifically interacting with these sequences were detected in activated cells regardless of whether the cells were treated with FK-506 or CsA [32].
  • Cyclosporin A (CsA) and FK506 (tacrolimus) are immunosuppresants that are widely used in organ transplantation [33].
  • Short-term CsA treatment did not prolong survival of allografts from farm pigs into minipigs.(ABSTRACT TRUNCATED AT 250 WORDS)[34]


  1. Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors. Towers, G.J., Hatziioannou, T., Cowan, S., Goff, S.P., Luban, J., Bieniasz, P.D. Nat. Med. (2003) [Pubmed]
  2. Bacterial cell wall-induced hepatic granulomas. An in vivo model of T cell-dependent fibrosis. Wahl, S.M., Hunt, D.A., Allen, J.B., Wilder, R.L., Paglia, L., Hand, A.R. J. Exp. Med. (1986) [Pubmed]
  3. Calcineurin acts in synergy with PMA to inactivate I kappa B/MAD3, an inhibitor of NF-kappa B. Frantz, B., Nordby, E.C., Bren, G., Steffan, N., Paya, C.V., Kincaid, R.L., Tocci, M.J., O'Keefe, S.J., O'Neill, E.A. EMBO J. (1994) [Pubmed]
  4. Transient cardiac expression of constitutively active Galphaq leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways. Mende, U., Kagen, A., Cohen, A., Aramburu, J., Schoen, F.J., Neer, E.J. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  5. Cyclophilin A is required for TRIM5{alpha}-mediated resistance to HIV-1 in Old World monkey cells. Berthoux, L., Sebastian, S., Sokolskaja, E., Luban, J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  6. Inhibition of calcineurin by infusion of CsA causes hyperphosphorylation of tau and is accompanied by abnormal behavior in mice. Yu, D.Y., Luo, J., Bu, F., Song, G.J., Zhang, L.Q., Wei, Q. Biol. Chem. (2006) [Pubmed]
  7. Individual differences in the in vitro response to cyclosporin A (CsA): possible heterogeneity in the involvement of the CD28-B7/BB1 pathway. Masy, E., Labalette-Houache, M., Dessaint, J.P. Thérapie. (1994) [Pubmed]
  8. Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. Irwin, W.A., Bergamin, N., Sabatelli, P., Reggiani, C., Megighian, A., Merlini, L., Braghetta, P., Columbaro, M., Volpin, D., Bressan, G.M., Bernardi, P., Bonaldo, P. Nat. Genet. (2003) [Pubmed]
  9. Two cytoplasmic candidates for immunophilin action are revealed by affinity for a new cyclophilin: one in the presence and one in the absence of CsA. Friedman, J., Weissman, I. Cell (1991) [Pubmed]
  10. Expression of heme oxygenase-1 can determine cardiac xenograft survival. Soares, M.P., Lin, Y., Anrather, J., Csizmadia, E., Takigami, K., Sato, K., Grey, S.T., Colvin, R.B., Choi, A.M., Poss, K.D., Bach, F.H. Nat. Med. (1998) [Pubmed]
  11. p53 transactivation of the HIV-1 long terminal repeat is blocked by PD 144795, a calcineurin-inhibitor with anti-HIV properties. Gualberto, A., Marquez, G., Carballo, M., Youngblood, G.L., Hunt, S.W., Baldwin, A.S., Sobrino, F. J. Biol. Chem. (1998) [Pubmed]
  12. Calcineurin Regulates Myocardial Function during Acute Endotoxemia. Joshi, M.S., Julian, M.W., Huff, J.E., Bauer, J.A., Xia, Y., Crouser, E.D. Am. J. Respir. Crit. Care Med. (2006) [Pubmed]
  13. Differential in vitro sensitivity of human tumor and normal cells to chemotherapeutic agents and resistance modulators. Nygren, P., Larsson, R. Int. J. Cancer (1991) [Pubmed]
  14. Vitamin E attenuates biochemical and morphological features associated with development of chronic pancreatitis. Gómez, J.A., Molero, X., Vaquero, E., Alonso, A., Salas, A., Malagelada, J.R. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) [Pubmed]
  15. Role of chronic inflammation in the promotion of prostatic hyperplasia in rats. Kessler, O.J., Keisari, Y., Servadio, C., Abramovici, A. J. Urol. (1998) [Pubmed]
  16. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Clipstone, N.A., Crabtree, G.R. Nature (1992) [Pubmed]
  17. FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin. O'Keefe, S.J., Tamura, J., Kincaid, R.L., Tocci, M.J., O'Neill, E.A. Nature (1992) [Pubmed]
  18. Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Fischer, G., Wittmann-Liebold, B., Lang, K., Kiefhaber, T., Schmid, F.X. Nature (1989) [Pubmed]
  19. Intrathymic differentiation of V gamma 3 T cells. Leclercq, G., Plum, J., Nandi, D., De Smedt, M., Allison, J.P. J. Exp. Med. (1993) [Pubmed]
  20. Targeted deletion of CX(3)CR1 reveals a role for fractalkine in cardiac allograft rejection. Haskell, C.A., Hancock, W.W., Salant, D.J., Gao, W., Csizmadia, V., Peters, W., Faia, K., Fituri, O., Rottman, J.B., Charo, I.F. J. Clin. Invest. (2001) [Pubmed]
  21. Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription. Hultsch, T., Albers, M.W., Schreiber, S.L., Hohman, R.J. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  22. Calcineurin controls nerve activity-dependent specification of slow skeletal muscle fibers but not muscle growth. Serrano, A.L., Murgia, M., Pallafacchina, G., Calabria, E., Coniglio, P., Lømo, T., Schiaffino, S. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  23. Negative transcriptional regulation of human interleukin 2 (IL-2) gene by glucocorticoids through interference with nuclear transcription factors AP-1 and NF-AT. Paliogianni, F., Raptis, A., Ahuja, S.S., Najjar, S.M., Boumpas, D.T. J. Clin. Invest. (1993) [Pubmed]
  24. Circulating monoclonal B cells expressing P glycoprotein may be a reservoir of multidrug-resistant disease in multiple myeloma. Pilarski, L.M., Belch, A.R. Blood (1994) [Pubmed]
  25. Recombinant NFAT1 (NFATp) is regulated by calcineurin in T cells and mediates transcription of several cytokine genes. Luo, C., Burgeon, E., Carew, J.A., McCaffrey, P.G., Badalian, T.M., Lane, W.S., Hogan, P.G., Rao, A. Mol. Cell. Biol. (1996) [Pubmed]
  26. Virus-induced murine diabetes. Enhancement by immunosuppression. Gould, C.L., McMannama, K.G., Bigley, N.J., Giron, D.J. Diabetes (1985) [Pubmed]
  27. An essential role for Bruton's [corrected] tyrosine kinase in the regulation of B-cell apoptosis. Anderson, J.S., Teutsch, M., Dong, Z., Wortis, H.H. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  28. Cellular basis of the role of diesel exhaust particles in inducing Th2-dominant response. Ohtani, T., Nakagawa, S., Kurosawa, M., Mizuashi, M., Ozawa, M., Aiba, S. J. Immunol. (2005) [Pubmed]
  29. Retina-specifically expressed novel subtypes of bovine cyclophilin. Ferreira, P.A., Hom, J.T., Pak, W.L. J. Biol. Chem. (1995) [Pubmed]
  30. Differential requirements for interleukin-2 distinguish the expression and activity of the cyclin-dependent kinases Cdk4 and Cdk2 in human T cells. Modiano, J.F., Domenico, J., Szepesi, A., Lucas, J.J., Gelfand, E.W. J. Biol. Chem. (1994) [Pubmed]
  31. Nuclear factor of activated T cells contains Fos and Jun. Jain, J., McCaffrey, P.G., Valge-Archer, V.E., Rao, A. Nature (1992) [Pubmed]
  32. The immunosuppressant FK-506 specifically inhibits mitogen-induced activation of the interleukin-2 promoter and the isolated enhancer elements NFIL-2A and NF-AT1. Banerji, S.S., Parsons, J.N., Tocci, M.J. Mol. Cell. Biol. (1991) [Pubmed]
  33. Neuroimmunophilins: novel neuroprotective and neuroregenerative targets. Guo, X., Dillman, J.F., Dawson, V.L., Dawson, T.M. Ann. Neurol. (2001) [Pubmed]
  34. Fetal pancreas transplantation in miniature swine. II. Survival of fetal pig pancreas allografts cultured at room temperature. Yoneda, K., Mullen, Y., Stein, E., Clare-Salzler, M., Ozawa, A., Shevlin, L., Danilovs, J. Diabetes (1989) [Pubmed]
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