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Calcineurin-Targeted Inhibition of Immune Reactivity

  • Chapter
Therapeutic Immunosuppression

Part of the book series: Immunology and Medicine Series ((IMME,volume 29))

Abstract

The modern era of transplantation began with the emergence of a potent immunosuppressive drug, cyclosporine (CsA). This drug had features unlike any previous drugs. CsA was soon joined by FK506 (FK), later named tacrolimus, an unrelated agent with many similar properties. The exploration of the actions of these drugs revealed new aspects of signal transduction in the T cell and many other cells. A third drug, rapamycin (sirolimus) differed in important ways from CsA and FK, but shared some properties and also elucidated a remarkable new pathway. These three drugs are derived from fungi and target intracellular proteins that are highly conserved through evolution, reflecting their important biological functions. The proteins targeted by these drugs include the binding proteins named immunophilins and the drug targets calcineurin (CN) and target of rapamycin. The ubiquity of these proteins raises the question of why these drugs affect the immune response relatively selectively. This chapter will review inhibition of the immune response by CsA and FK, drugs that inhibit CN phosphatase activity.

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References

  1. Borel JF, Feurer C, Gubler HJ, Stahelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents and Actions 1976;6:468–75.

    Article  PubMed  CAS  Google Scholar 

  2. Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H. FK-506, a novel immunosuppressant isolated from a streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot 1987;40:1249–55.

    CAS  Google Scholar 

  3. Tocci MJ, Matkovich DA, Collier KA, Kwok P, Dumont F, Lin S, Degudicibus S, Siekierka JJ, Chin J, Hutchinson NI. The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol 1989; 143:718–26.

    PubMed  CAS  Google Scholar 

  4. Elliot JF, Lin Y, Mizel SB, Bleackley RC, Harnish DG, Paetkau V. Induction of interleukin 2 messenger RNA inhibited by Cyclosporine A. Science 1984;226: 1439–41.

    Google Scholar 

  5. Kronke M, Leonard WJ, Depper JM, Arya SK, Wong-Staal F, Gallo RC, Waldman TA, Green WC. Cyclosporine A inhibits T cell growth factor gene expression at the level of mRNA transcription. Proc Natl Acad Sci USA 1984;81:5214–8.

    Article  PubMed  CAS  Google Scholar 

  6. Handschumacher RE, Harding MW, Rice J, Drugge RJ, Speicher DW. Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science 1984;226:544–7.

    Article  PubMed  CAS  Google Scholar 

  7. Harding MW, Galat A, Uehling DE, Schreiber SL. A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature 1989;341: 758–60.

    Article  PubMed  CAS  Google Scholar 

  8. Fischer G, Wittmann-Liebold K, Lang T, Kiefhaber T, Schmid FX. Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature 1989; 337:476–

    Article  PubMed  CAS  Google Scholar 

  9. Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 1991;66:807–15

    Article  PubMed  CAS  Google Scholar 

  10. Clipstone NA, Crabtree GR. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 1992;357:695–7.

    Article  PubMed  CAS  Google Scholar 

  11. Emmel EA, Verweij CL, Durand DB, Higgins KM, Lacy E, Crabtree GR. Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation. Science 1989;246:1617

    Article  PubMed  CAS  Google Scholar 

  12. Hultsch T, Albers MW, Schreiber SL, Hohman RJ. Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription. Proc Natl Acad Sci USA 1991;88:6229–33.

    Article  PubMed  CAS  Google Scholar 

  13. Wicker LS, Boltz RC, Matt V. Suppression of B-cell activation by cyclosporin-A, FK506, and rapamycin. Eur J Immunol 1990;20(2277):2283

    Google Scholar 

  14. Batiuk TD, Pazderka F, Enns J, DeCastro L, Halloran PF. Cyclosporine inhibition of calcineurin activity in human leukocytes in vivo is rapidly reversible. J Clin Invest 1995;96:1254–60.

    Article  PubMed  CAS  Google Scholar 

  15. Foxwell BMJ, Mackie A, Ling V, Ryffel B. Identification of the multi-drug resistance-related P-glycoprotein as a cyclosporine binding protein. Mol Pharmacol 1989;36:543–6.

    PubMed  CAS  Google Scholar 

  16. Atkison P, Joubert G, Barron A, Grant D, Paradis K, Seidman E, Wall W, Rosenberg H, Howard J, Williams S, et al. Hypertrophic cardiomyopathy associated with tacrolimus in paediatric transplant patients. Lancet 1995;345:894–6.

    Article  PubMed  CAS  Google Scholar 

  17. Sigal NH, Dumont F, Durette P, Siekierka JJ, Peterson L, Rich DH, Dunlap BE, Staruch MJ, Melino MR, Koprak SL, et al. Is cyclophilin involved in the immunosuppressive and nephrotoxic mechanism of action of cyclosporin A? J Exp Med 1991;173:619–28.

    Article  PubMed  CAS  Google Scholar 

  18. Arello F, Krupp P. Muscular disorders associated with cyclosporin. Lancet 1991; 337:915

    Article  Google Scholar 

  19. Liu J, Albers MW, Wandless TJ, Luan S, Alberg DG, Belshaw PJ, Cohen P, MacKintosh C, Kless CB, Schreiber SL. Inhibition of T cell signaling by immunophilin-ligand complexes correlates with loss of calcineurin phosphatase activity. Biochemistry 1992;31:3896–901.

    Article  PubMed  CAS  Google Scholar 

  20. Fruman DA, Klee CB, Bierer BE, Burakoff SJ. Calcineurin phosphatase activity in T lymphocytes is inhibited by FK506 and cyclosporin A. Proc Natl Acad Sci USA 1992;89:3686–90.

    Article  PubMed  CAS  Google Scholar 

  21. Griffith JP, Kim JL, Kim EE, Sintchak MD, Thomson JA, Fitzgibbon MJ, Fleming MA, Caron PR, Hsiao K, Navia MA. X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex. Cell 1995;82: 507–22.

    Article  PubMed  CAS  Google Scholar 

  22. Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Kalish VJ, Tucker KD, Showalter RE, Moomaw EW, et al. Crystal structure of human calcineurin and the human FKBP12-FK506-calcineurin complex. Nature 1995;378:641–4

    Article  PubMed  CAS  Google Scholar 

  23. Cardenas ME, Muir RS, Breuder T, Heitman J. Targets of immunophilin-immunosuppressant complexes are distinct highly conserved regions of calcineurin A. EMBO J 1995;14(12):2772–83.

    PubMed  CAS  Google Scholar 

  24. Bram RJ, Hung DT, Martin PK, Schreiber SL, Crabtree GR. Identification of the immunophilins capable of mediating inhibition of signal transduction by cyclosporin A and FK506: roles of calcineurin binding and cellular location. Mol Cell Biol 1993;13(8):4760–9.

    PubMed  CAS  Google Scholar 

  25. Sewell TJ, Lam E, Martin MM, Seszyk J, Weidner J, Calaycay J, Griffin P, Williams H, Hung S, Cryan J, et al. Inhibition of calcineurin by a novel FK-506-binding protein. J Biol Chem 1994;269(33):21094–102.

    PubMed  CAS  Google Scholar 

  26. Baughman G, Wiederrecht GJ, Chang F, Martin MM, Bourgeois S. Tissue distribution and abundance of human FKBP51, an FK506-binding protein that can mediate calcineurin inhibition. Biochem Biophys Res Commun 1997;232:437–43.

    Google Scholar 

  27. Nigam SK, Jin Y-J, Jin M-J, Bush KT, Bierer BE, Burakoff SJ. Localization of the FK506-binding protein, FKBP 13, to the lumen of the endoplasmic reticulum. Biochem J 1993;294:511–5.

    Google Scholar 

  28. Stewart AA, Ingebritsen TS, Cohen P. The protein phosphatases involved in cellular regulation. 5. Purification and proterties of a Ca2+calmodulin-dependent protein phosphatase (2B) from rabbit skeletal muscle. Eur J Biochem 1983; 132: 289–95.

    Article  PubMed  CAS  Google Scholar 

  29. Stewart AA, Ingebritsen TS, Manalan A, Klee CB, Cohen P. Discovery of Ca2+-and calmodulin-dependent protein phosphatase. Probable identity with calcineurin (CaM-BP80). FEBS Lett 1982;137(1):80–4.

    Article  PubMed  CAS  Google Scholar 

  30. Klee CB, Draetta GF, Hubbard MJ. Calcineurin [review]. Advances Enzymology & Related Areas of Molecular Biology 1988;61:149–200.

    CAS  Google Scholar 

  31. Kincaid RL. Shenolikar S, Nairn AC, editors.Advances in Second Messenger and Phosphoprotein Research. New York, NY: Raven Press; 1993; 1, Calmodulin-dependent protein phosphatases from microorganisms to man. A study in structural conservatism and biological diversity, p. 1-23.

    Google Scholar 

  32. Chernoff J, Sells MA, Li HC. Characterization of phosphotyrosyl-protein phosphatase activity associated with calcineurin. Biochem Biophys Res Commun 1984; 121:141–8.

    Google Scholar 

  33. Klee CB, Krinks MH. Purification of cyclic 3’, 5’-nucleotide phosphodiesterase inhibitory protein by affinity chromatography on activator protein coupled to Sepharose. Biochemistry 1979;17:120–6.

    Google Scholar 

  34. Muramatsu T, Kincaid RL. Molecular cloning and chromosomal mapping of the human gene for the testis-specific catalytic subunit of calmodulin-dependent protein phosphatase (calcineurin A). Biochem Biophys Res Commun 1992; 188(1): 265–71.

    Article  PubMed  CAS  Google Scholar 

  35. Klee CB, Ren H, Wang X. Regulation of the calmodulin-stimulated protein phosphatase, calcineurin. J Biol Chem 1998;273(22): 13367–70.

    Article  PubMed  CAS  Google Scholar 

  36. Kincaid RL, Nightingale MS, Martin BM. Characterization of a cDNA clone encoding the calmodulin-binding domain of mouse brain calcineurin. Proc Natl Acad Sci USA 1988;85:8983–7.

    Article  PubMed  CAS  Google Scholar 

  37. Kakalis LT, Kennedy M, Sikkink R, Rusnak F. Characterization of the calciumbinding site of calcineurin B. FEBS Lett 1995;362:55–8.

    Article  PubMed  CAS  Google Scholar 

  38. Hashimoto Y, Perrino BA, Soderling TR. Identification of an autoinhibitory domain in calcineurin. J Biol Chem 1990;265:1924–7.

    Google Scholar 

  39. Hubbard MJ, Klee CB. Functional domain structure of calcineurin A: mapping by limited proteolysis. Biochemistry 1989;28:1868–74.

    Article  PubMed  CAS  Google Scholar 

  40. Perrino BA, Ng LY, Soderling TR. Calcium regulation of calcineurin phosphatase activity by its B subunit and calmodulin. J Biol Chem 1995;270(1):340–6.

    Article  PubMed  CAS  Google Scholar 

  41. Ueki K, Muramatsu T, Kincaid RL. Structure and expression of two isoforms of the murine calmodulin-dependent protein phosphatase regulatory subunit (calcineurin B). Biochem Biophys Res Commun 1992;187(1):537–43.

    Article  PubMed  CAS  Google Scholar 

  42. Mukai H, Chang C-D, Tanaka H, Ito A, Kuno T, Tanaka C. cDNA cloning of a novel testis-specific calcineurin B-like protein. Biochem Biophys Res Commun 1991; 179(3): 1325–30.

    Article  PubMed  CAS  Google Scholar 

  43. King MM, Huang CY. Activation of calcineurin by nickel ions. Biochem Biophys Res Commun 1983;114:955–61.

    Article  PubMed  CAS  Google Scholar 

  44. King MM, Huang CY. The calmodulin-dependent activation and deactivation of the phosphoprotein phosphatase, calcineurin, and the effect of nucleotides, pyrophosphate, and divalent metal ions. J Biol Chem 1984;259:8847–56.

    PubMed  CAS  Google Scholar 

  45. Wang X, Culotta VC, Klee CB. Superoxide dismutase protects calcineurin from inactivation. Nature 1996;383:434–7.

    Article  PubMed  CAS  Google Scholar 

  46. Fanger CM, Hoth M, Crabtree GR, Lewis RS. Characterization of T cell mutants with defects in capacitative calcium entry: genetic evidence for the physiological roles of CRAC channels. J CeU Biol 1995;131(3):655–67.

    Article  CAS  Google Scholar 

  47. Berridge MJ. Calcium signalling and cell proliferation [review]. BioEssays 1995; 17(6):491–500.

    Article  PubMed  CAS  Google Scholar 

  48. Cardenas ME, Heitman J. Means AP, editors.Advances in Second Messenger and Phosphoprotein Research. New York, NY: Raven Press, Ltd.; 1995; 9, Role of calcium in T-lymphocyte activation. p. 281–98.

    Google Scholar 

  49. Pawson T, Scott JD. Signaling through scaffold, anchoring, and adaptor proteins. Science 1997;278:2075–80.

    Article  PubMed  CAS  Google Scholar 

  50. Mochly-Rosen D. Localization of protein kinases by anchoring proteins: a theme in signal transduction. Science 1995;268:247–51.

    Article  PubMed  CAS  Google Scholar 

  51. Coghlan VM, Perrino BA, Howard M, Langeberg LK, Hicks JB, Gallatin WM, Scott JD. Association of protein kinase A and protein phosphatase 2B with a common anchoring protein. Science 1995;267:108–11.

    Google Scholar 

  52. Shibasaki F, Kondo E, Akagi T, McKeon F. Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2. Nature 1997;386:728–31.

    Article  PubMed  CAS  Google Scholar 

  53. Cameron AM, Steiner JP, Roskams AJ, Ali SM, Ronnett GV, Snyder SH. Calcineurin associated with the inositol 1,4,5-triphosphate receptor-FKBP12 complex modulates Ca2+ flux. CeU 1995;83:463–72.

    CAS  Google Scholar 

  54. Del’Acqua ML, Faux MC, Thorburn J, Thorburn A, Scott JD. Membrane-targeting sequences on AKAP79 bind phosphatidylinositol-4, 5-biphosphate. EMBO J 1998;17:2246–60

    Article  Google Scholar 

  55. Can DW, Hausken ZE, Fraser ID, Stofko-Hahn RE, Scott JD. Association of the type II cAMP-dependent protein kinase with a human thyroid RII-anchoring protein. J Biol Chem 1992;267:13376–82.

    Google Scholar 

  56. Faux MC, Scott JD. Molecular glue: kinase anchoring and scaffold proteins [review]. Cell 1996;85(9):12

    Google Scholar 

  57. Kashishian A, Howard M, Loh C, Gallatin WM, Hoekstra MF, Lai Y. AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region. J Biol Chem 1998;273(42):27412–9.

    Article  PubMed  CAS  Google Scholar 

  58. Krajewski S, Tanaka S, Takayama S, Schibler MJ, Fenton W, Reed JC. Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. Cancer Res 1993;53(19):4701–14.

    PubMed  CAS  Google Scholar 

  59. Linette GP, Li Y, Roth K, Korsmeyer SJ. Cross talk between cell death and cell cycle progression: Bcl-2 regulates NFAT-mediated rejection. Proc Natl Acad Sci USA 1996;93:9545–52.

    Article  PubMed  CAS  Google Scholar 

  60. Shibasaki F, McKeon F. Calcineurin functions in Ca2+-activated cell death in mammalian cells. J CeU Biol 1995;131(3):735–43.

    Article  CAS  Google Scholar 

  61. Beals CR, Sheridan CM, Turck CW, Gardner P, Crabtree GR. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science 1997;275:1930–3.

    Article  PubMed  CAS  Google Scholar 

  62. Shaw KTY, Ho AM, Raghavan A, Kim J, Jain J, Park J, Sharma S, Rao A, Hogan PG. Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells. Proc Natl Acad Sei USA 1995;92: 11205–9.

    Article  CAS  Google Scholar 

  63. Beals CR, Clipstone NA, Ho SN, Crabtree GR. Nuclear localization of NF-ATc by a calcineurin-dependent, cyclosporin-sensitive intramolecular interaction. Genes Dev 1997;11:824–34.

    Article  PubMed  CAS  Google Scholar 

  64. Zhu J, Shibasaki F, Price R, Guillemot J-C, Yano T, Dotsch V, Wagner G, Ferrara P, McKeon F. Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK-1. CeU 1998;93:851–61.

    CAS  Google Scholar 

  65. Chow C-W, Rincón M, Cavanagh J, Dickens M, Davis RJ. Nuclear accumulation of NFAT4 opposed by the JNK signal transduction pathway. Science 1997;278: 1638–41.

    Article  PubMed  CAS  Google Scholar 

  66. Chen L, Glover JNM, Hogan PG, Rao A, Harrison SC. Structure of the DNA-binding domains from NFAT, Fos and Jun bound specifically to DNA. Nature 1998; 392:42–8.

    Article  PubMed  CAS  Google Scholar 

  67. Kehlenbach RH, Dickmanns A, Gerace L. Nucleocytoplasmic shuttling factors including Ran and crml mediate nuclear export of NFAT in vivo. J Cell Biol 1998; 141(4): 863–74.

    Article  PubMed  CAS  Google Scholar 

  68. Rao A, Luo C, Hogan PG. Transcription factors of the NFAT family: regulation and function. Ann Rev Immunol 1997;15:707–47.

    Google Scholar 

  69. Ho I-C, Kim JHJ, Rooney JW, Spiegelman BM, Glimcher LH. A potential role for the nuclear factor of activated T cells family of transcriptional regulatory proteins in adipogensis. Proc Natl Acad Sci USA 1998;95(26): 15537–41.

    Article  PubMed  CAS  Google Scholar 

  70. Ranger AM, Grusby MJ, Hodge MR, Gravallese EM, de la Brousse FC, Hoey T, Mickanin C, Baldwin HS, Glimcher LH. The transcription factor NF-ATc is essential for cardiac valve formation. Nature 1998;392:186–90.

    Article  PubMed  CAS  Google Scholar 

  71. de la Pompa JL, Timmerman LA, Takimoto H, Yoshida H, Elia AJ, Samper E, Potter J, Wakeham A, Marengere L, Langille BL, et al. Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum. Nature 1998; 392:182–6.

    Article  PubMed  Google Scholar 

  72. Yoshida H, Nisina H, Takimoto H, Marengere LEM, Wakeham AC, Bouchard D, Kong Y-Y, Ohteki T, Shahinian A, Bachmann M, et al. The transcription factor NF-ATcl regulates lymphocyte proliferation and Th2 cytokine production. Immunity 1998;8:115–24.

    Article  PubMed  CAS  Google Scholar 

  73. Viola JPB, Kiani A, Bozza PT, Rao A. Regulation of allergic inflammation and eosinophil recruitment in mice lacking the transcription factor NFAT1: role of interleukin-4 (IL-4) and IL-5. Blood 1998;91(7):2223–30.

    PubMed  CAS  Google Scholar 

  74. Ranger AM, Hodge MR, Gravallese EM, Oukka M, Davidson L, Alt FW, de la Brousse FC, Hoey T, Grusby M, Glimcher LH. Delayed lymphoid repopulation with effects in IL-4 driven responses produced by inactivation of NF-ATc. Immunity 1998;8:125–34.

    Article  PubMed  CAS  Google Scholar 

  75. Ranger AM, Oukka M, Rengarajan J, Glimcher LH. Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development. Immunity 1998;9:627–35.

    Article  PubMed  CAS  Google Scholar 

  76. Lopez-Rodriguez C, Aramburu J, Rakeman AA, Rao A. NFAT5, a constitutively nuclear NFAT protein that does not cooperate with Fos and Jun. Proc Natl Acad Sci USA 1999;96:7214–9.

    Article  PubMed  CAS  Google Scholar 

  77. Sugimoto T, Stewart S, Guan KL. The calcium/calmodulin-dependent protein phosphatase calcineurin is the major Elk-1 phosphatase. J Biol Chem 1997;272(47): 29415–8.

    Article  PubMed  CAS  Google Scholar 

  78. Hill CS, Treisman R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell 1995;80:199–211.

    Article  PubMed  CAS  Google Scholar 

  79. Lino M. Dynamic regulation of intracellular calcium signals through calcium release channels [review]. Mol Cell Biochem 1999;190(l-2):185–90.

    Google Scholar 

  80. Ferris CD, Huganir RL, Bredt DS, Cameron AM, Snyder SH. Inositol triphosphate receptor: phosphorylation by protein kinase C and calcium calmodulin-dependent protein kinases in reconstituted lipid vesicles. Proc Natl Acad Sci USA 1991; 88:2232–5.

    Article  PubMed  CAS  Google Scholar 

  81. Cameron AM, Steiner JP, Sabatini DM, Kaplin AI, Walensky LD, Snyder SH. Immunophilin FK506 binding protein associated with inositol 1,4,5-triphosphate receptor modulates calcium flux. Proc Natl Acad Sci USA 1995;92:1784–8.

    Article  PubMed  CAS  Google Scholar 

  82. Marietta MA. Nitric oxide synthase: aspects concerning structure and catalysis. Cell 1994;78:927–30.

    Article  CAS  Google Scholar 

  83. Dawson TM, Steiner JP, Dawson VL, Dinerman JL, Uhl GR, Snyder SH. Immunosup-pressant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity. Proc Natl Acad Sci USA 1993;90(21):9808–12.

    Article  PubMed  CAS  Google Scholar 

  84. Yamamoto H, Fukunaga K, Tanaka E, Miyamoto E. Ca2+-and calmodulin-dependent phosphorylation of microtubule-associated protein 2 and % factor, and inhibtion of microtubule assembly. J Neurochemistry 1983;41:1119–25.

    Article  CAS  Google Scholar 

  85. Goto S, Yamamoto H, Fukunaga K, Iwasa T, Matsukado Y, Miyamoto E. Dephosphorylation of microtubule-associated protein 2, τ factor, and tubulin by calcineurin. J Neurochemistry 1985;45:276–83.

    Article  CAS  Google Scholar 

  86. DeCamilli P, Harris JM, Jr., Huttner WB, Greegard P. Synapsin (protein I), a nerve terminal-specific phosphoprotein. II. Its specific association with synaptic vesicles demonstrated by immunocytochemistry in agarose-embedded synaptosomes. J Cell Biol 1983;96:1355–73.

    Article  PubMed  Google Scholar 

  87. Llinas R, McGuiness TL, Leonard CS, Sugimori M, Greengard P. Intraterminal injection of synapsin I or calcium/calmodulin-dependent protein kinase II alters neurotransmitter release at the squid giant synapse. Proc Natl Acad Sci USA 1985;82:3035–9.

    Article  PubMed  CAS  Google Scholar 

  88. Huttner WB, Greengard P. Multiple phosphorylation site in protein I and their differential regulation by cyclic AMP and calcium. Proc Natl Acad Sci USA 1979; 76:5402–6.

    Article  PubMed  CAS  Google Scholar 

  89. Kennedy MB, Greengard P. Two calcium/calmodulin-dependent protein kinases, which are highly concentrated in brain, phosphorylate protein I at distinct sites. Proc Natl Acad Sci USA 1981;78:1293–7.

    Article  PubMed  CAS  Google Scholar 

  90. De Camilli P, Takei K. Molecular mechanisms in synaptic vesicle endocytosis and recycling. Neuron 1996;16:481–6.

    Google Scholar 

  91. Liu J, Sim ATR, Robinson PJ. Calcineurin inhibition of dynamin I GTPase activity coupled to nerve terminal depolarization. Science 1994;265:970–3.

    Google Scholar 

  92. Nichols RA, Suplick GR, Brown JM. Calcineurin-mediated protein dephosphorylation in brain nerve terminals regulates the release of glutamate. J Biol Chem 1994;269(38):23817–23.

    PubMed  CAS  Google Scholar 

  93. Frantz B, Nordby EC, Bren G, Steffan N, Paya CV, Kincaid RL, Tocci MJ, O’Keefe SJ, O’Neill EA. Calcineurin acts in synergy with PMA to inactivate IkB/MAD3, an inhibitor of NF-kB. EMBO J 1994;13:861–70.

    PubMed  CAS  Google Scholar 

  94. Werlen G, Jacinto E, Xia Y, Karin M. Calcineurin preferentially synergizes with PKC-theta to activate JNK and IL-2 promoter in T lymphocytes. EMBO J 1998; 17(11):3101–11.

    Article  PubMed  CAS  Google Scholar 

  95. Zhang W, Zimmer G, Chen J, Ladd D, Li E, Alt FW, Wiederrecht G, Cryan J, O’Neill EA, Seidman CE, et al. T cell responses in calcineurin A a-deficient mice. J Exp Med 1996;183:413–20.

    Google Scholar 

  96. Zhu J, McKeon F. NF-AT activation requires suppressin of crml-dependent export by calcineurin. Nature 1999;398:256–60.

    Article  PubMed  CAS  Google Scholar 

  97. Liu S, Liu P, Borras A, Chatila T, Speck SH. Cyclosporin A-sensitive induction of the Epstein-Barr virus lytic switch is mediated via a novel pathway involving a MEF2 family member. EMBO J 1997;16:143–53.

    Article  PubMed  CAS  Google Scholar 

  98. Black BL, Olson EN. Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Ann Rev Cell Dev Biol 1998; 14:167–96.

    Article  CAS  Google Scholar 

  99. Sussman MA, Lim HW, Gude N, Taigen T, Olson EN, Robbins J, Colbert MC, Gualberto A, Wieczorek DF, Molkentin JD. Prevention of cardiac hypertrophy in mice by calcineurin inhibition. Science 1998;281:1690–3.

    Google Scholar 

  100. Mokentin JD, Lu J-R, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 1998;93:215–28.

    Article  Google Scholar 

  101. Zhang W, Kowal RC, Rusnak F, Sikkink RA, Olson EN, Victor RG. Failure of calcineurin inhibitors to prevent pressure-overload left ventribular hypertrophy in rats. Circ Res 1999;84:722–8.

    Article  PubMed  CAS  Google Scholar 

  102. Meguro T, Hong C, Asai K, Takagi G, McKinsey TA, Olson EN, Vatner SF. Cyclosporine attenuates pressure-overload hypertrophy in mice while enhancing susceptibility to decompensation and heart failure. Circ Res 1999;84:735–40.

    Article  PubMed  CAS  Google Scholar 

  103. Mulkey RM, Endo S, Shenolikar S, Malenka RC. Involvement of a calcineurin/ inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature 1994;369:486–8.

    Article  PubMed  CAS  Google Scholar 

  104. Bito H, Deisseroth K, Tsien RW. CREB phosphorylation and dephosphorylation: a Ca2+ and stimulus duration-dependent switch for hippocampal gene expression. CeU 1996;87:1203–14.

    CAS  Google Scholar 

  105. Enslen H, Sun P, Brickey D, Soderling SH, Klamo E, Soderling TR. Characterisation of Ca2+/calmodulin-dependent protein kinase IV: role of transcriptional regulation. J Biol Chem 1994;269:15520–7.

    PubMed  CAS  Google Scholar 

  106. Schiaffino S, Riggiani C. Molecular diversity of myofibrillar proteins: gene regulation and functional significance [review]. Physiol Rev 1996;76:371–423.

    PubMed  CAS  Google Scholar 

  107. Hoey T, Sun Y-L, Williamson K, Xu X. Isolation of two new members of the NF-AT gene family and functional characterization of the NF-AT proteins. Immunity 1995;2:461–72

    Article  PubMed  CAS  Google Scholar 

  108. Chin ER, Olson EN, Richardson JA, Yang Q, Humphries C, Shelton JM, Wu H, Zhu W, Bassel-Duby R, Williams RS. A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev 1998; 12:2499–509.

    Article  PubMed  CAS  Google Scholar 

  109. Musarò A, McCullagh KJA, Naya FJ, Olson EN, Rosenthal N. IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. Nature 1999;400:581

    Article  PubMed  Google Scholar 

  110. Dunn SE, Burns JL, Michel RN. Calcineurin is required for skeletal muscle hypertrophy. J Biol Chem 1999;274:21908–12.

    Article  PubMed  CAS  Google Scholar 

  111. Letterio JJ, Roberts AB. Regulation of immune responses by TGF-b. Ann Rev Immunol 1998;16:136–61.

    Article  Google Scholar 

  112. Bottinger EP, Letterio JJ, Roberts AB. Biology of TGF-β in knockout and transgenic mouse models. Kidney Int 1997;51:1355–60.

    Article  PubMed  CAS  Google Scholar 

  113. Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K, Lagman M, Shimbo T, Suthanthiran M. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 1999;397:530–4.

    Article  PubMed  CAS  Google Scholar 

  114. Khanna A, Kapur S, Sharma V, Li B, Suthanthiran M. In vivo hyperexpression of transforming growth factor-βl in mice: stimulation by cyclosporine. Transplantation 1997;63(7): 1037–9.

    Article  PubMed  CAS  Google Scholar 

  115. Shin G-T, Khanna A, Ding R, Sharma VK, Lagman M, Li B, Suthanthiran M. In vivo expression of transforming growth factor-bl in humans. Transplantation 1998;65(3):313–8.

    Article  PubMed  CAS  Google Scholar 

  116. Kirk AD, Jacobson LM, Heisey DM, Fass NA, Sollinger HW, Pirsch JD. Posttransplant diastolic hypertension. Transplantation 1997;64(12): 1716–20.

    Article  PubMed  CAS  Google Scholar 

  117. Shihab FS, Andoh TF, Tanner AM, Noble NA, Border WA, Franceschini N, Bennett WM. Role of transforming growth factor-βl in experimental chronic cyclosporine nephropathy. Kidney Int 1996;49:1141–51.

    Article  PubMed  CAS  Google Scholar 

  118. Shihab FS, Bennett WM, Tanner AM, Andoh TF. Mechanism of fibrosis in experimental tacrolimus nephrotoxicity. Transplantation 1997;64(12): 1829–37.

    Article  PubMed  CAS  Google Scholar 

  119. Khanna A, Cairns V, Hosenpud JD. Tacrolimus induces increased expression of transforming growth factor-βl in mammalian lymphoid as well as nonlymphoid cells. Transplantation 1999;67:614–9.

    Article  PubMed  CAS  Google Scholar 

  120. Kung L, Halloran PF. Immunophilins may limit calcineurin inhibition by cyclosporine and tacrolimus at high drug concentrations. Transplantation 2000;70(2): 327–35.

    Article  PubMed  CAS  Google Scholar 

  121. Aramburu J, Garcia-Cozar F, Raghavan A, Okamura H, Rao A, Hogan PG. Selective inhibition of NFAT activation by a peptide spanning the calcineurin targeting site of NFAT. Molecular Cell 1998; 1:627–37.

    Article  PubMed  CAS  Google Scholar 

  122. Aramburu J, Yaffe MB, López-Rodriguez C, Cantley LC, Hogan PG, Rao A. Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A. Science 1999;285:2129–33.

    Article  PubMed  CAS  Google Scholar 

  123. Jephthah-Ochola J, Urmson J, Farkas S, Halloran PF. Regulation of MHC in vivo. Bacterial lipopolysaccharide induces class I and II MHC products in mouse tissues by a T cell independent, cyclosporine sensitive mechanism. J Immunol 1988;141:792–800.

    PubMed  CAS  Google Scholar 

  124. Bennett PC, Singaretnam LG, Zhao W-Q, Lawen A, Ng KT. Peptidyl-prolyl-cis/ trans-isomerase activity may be necessary for memory formation. FEBS Lett 1998;431:386–90.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Nephrology & Immunology, University of Alberta, Edmonton, Alberta, Canada

    Lina Kung & Philip F. Halloran

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  1. Lina Kung
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  2. Philip F. Halloran
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  1. University of Pittsburgh, Pittsburgh, PA, USA

    Angus W. Thomson

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© 2001 Springer Science+Business Media Dordrecht

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Kung, L., Halloran, P.F. (2001). Calcineurin-Targeted Inhibition of Immune Reactivity. In: Thomson, A.W. (eds) Therapeutic Immunosuppression. Immunology and Medicine Series, vol 29. Springer, Dordrecht. https://doi.org/10.1007/978-94-010-0765-8_1

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  • DOI: https://doi.org/10.1007/978-94-010-0765-8_1

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