Summary
Antigen presentation induces lymphokine gene expression in T cells and an autocrine stimulatory pathway leading to cell growth and proliferation. Cyclosporin A (CsA) and FK-506, two potent, clinically relevant immunosuppressive compounds, function by preventing lymphokine production, particularly interleukin-2. These compounds act at the level of transcription by inhibiting the activation of a set of transcription factors that are required for initiation of lymphokine gene expression. Several of these factors have been the subject of intense scrutiny. Some, such as NF-AT (nuclear factor of activated T cells) are cell type specific, while others, such as NF-κB, are ubiquitously expressed. These factors do not share a common mechanism of activation, but calcineurin, a Ca2+-dependent phosphoprotein phosphatase plays a central role in the activation of each of them. Thus, not only are these immunosuppressive drugs clinically important, but they have served as unique probes of the signal transduction pathways that lead to activation of specific transcription factors involved in lymphokine gene expression.
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Abbreviations
- ARRE-1:
-
antigen receptor response element 1
- CD28-RE:
-
CD28-responsive element
- CsA:
-
cyclosporin A
- IL-2:
-
interleukin-2
- OAP:
-
octamer-associated protein
- Oct-1:
-
octamer transcription factor-1
- PMA:
-
phorbol myristate acetate
- PKC:
-
protein kinase C
References
Sigal, N.H. and Dumont, F.J., Annu. Rev. Immunol., 10 (1992) 519.
Kahan, B.D., New Engl. J. Med., 321 (1989) 1725.
Shapiro, R., Fung, J.J., Jain, A.B., Parks, P., Todo, S. and Starzl, T.E., Transplant. Proc., 22 (1990) 35.
Lin, C.S., Boltz, R.C., Siekierka, J.J. and Sigal, N.H., Cell. Immunol., 133 (1991) 269.
Tocci, M.J., Matkovich, D.A., Collier, K.A., Kwok, P., Dumont, F., Lin, C.S., DeGudicibus, S., Siekierka, J.J., Chin, J. and Hutchinson, N.I., J. Immunol., 143 (1989) 718.
Mercep, M., Noguchi, P.D. and Ashwell, J.D., J. Immunol., 142 (1989) 4085.
Shi, Y.F., Sahai, B.M. and Green, D.R., Nature, 339 (1989) 625.
Staruch, M.J., Sigal, N.H. and Dumont, F.J., Int. J. Immunopharmacol., 13 (1991) 677.
Bierer, B.E., Schreiber, S.L. and Burakoff, S.J., Eur. J. Immunol., 21 (1991) 439.
Hultsch, T., Albers, M.W., Schreiber, S.L. and Hohman, R.J., Proc. Natl. Acad. Sci. USA, 88 (1991) 6229.
Forrest, M.J., Jewell, M.E., Koo, G.C. and Sigal, N.H., Biochem. Pharmacol., 42 (1991) 1121.
Nossal, G.J.V., Science, 245 (1989) 147.
Rajewsky, K. and Von Boehmer, H., Curr. Opin. Immunol., 5 (1993) 175.
Weiss, A., Imboden, J., Hardy, K., Manger, B., Terhorst, C. and Stobo, J., Annu. Rev. Immunol., 4 (1986) 593.
Ullman, K.S., Northrop, J.P., Verweij, C.L. and Crabtree, G.R., Annu. Rev. Immunol., 8 (1990) 421.
Crabtree, G.R., Science, 243 (1989) 355.
Kronke, M., Leonard, W.J., Depper, J.M., Arya, S.K., Wong, S.F., Gallo, R.C., Waldmann, T.A. and Greene, W.C., Proc. Natl. Acad. Sci. USA, 81 (1984) 5214.
Elliott, J.F., Lin, Y., Mizel, S.B., Bleackley, R.C., Harnish, D.G. and Paetkau, V., Science, 226 (1984) 1439.
Mizushima, Y., Kosaka, H., Sakuma, S., Kanda, K., Itoh, K., Osugi, T., Mizushima, A., Hamaoka, T., Yoshida, H., Sobue, K. and Fujiwara, H., J. Biochem., 102 (1987) 1193.
Granelli, P.A., Andrus, L. and Steinman, R.M., J. Exp. Med., 163 (1986) 922.
Kay, J.E. and Benzie, C.R., Immunol. Lett., 23 (1990) 155.
June, C.H., Ledbetter, J.A., Gillespie, M.M., Lindsten, T. and Thompson, C.B., Mol. Cell. Biol., 7 (1987) 4472.
Mattila, P.S., Ullman, K.S., Fiering, S., Emmel, E.A., McCutcheon, M., Crabtree, G.R. and Herzenberg, L.A., EMBO J., 9 (1990) 4425.
Smith, K.A., Science, 240 (1988) 1169.
Dumont, F.J., Staruch, M.J., Koprak, S.L., Melino, M.R. and Sigal, N.H., J. Immunol., 144 (1990) 251.
Durand, D.B., Bush, M.R., Morgan, J.G., Weiss, A. and Crabtree, G.R., J. Exp. Med., 165 (1987) 395.
Durand, D.B., Shaw, J.-P., Bush, M.R., Replogle, R.E., Belagaje, R. and Crabtree, G.R., Mol. Cell. Biol., 8 (1988) 1715.
Kamps, M.P., Corcoran, L., LeBowitz, J.H. and Baltimore, D., Mol. Cell. Biol., 10 (1990) 5464.
O'Neill, E.A., Frantz, B., Nordby, E.C. and Tocci, M.J., Transplant. Proc., 23 (1991) 2862.
Williams, T.M., Moolten, D., Burlein, J., Romano, J., Bhaerman, R., Godillot, A., Mellon, M., Rauscher, F.J. and Kant, J.A., Science, 254 (1991) 1791.
Ullman, K.S., Flanagan, W.M., Edwards, C.A. and Crabtree, G.R., Science, 254 (1991) 558.
Northrop, J.P., Crabtree, G.R. and Mattila, P.S., J. Exp. Med., 175 (1992) 1235.
Riegel, J.S., Corthesy, B., Flanagan, W.M. and Crabtree, G.R., Chem. Immunol., 51 (1992) 266.
Fraser, J.D., Irving, B.A., Crabtree, G.R. and Weiss, A., Science, 251 (1991) 313.
Verweij, C.L., Geerts, M. and Aarden, L.A., J. Biol. Chem., 266 (1991) 14179.
Hoyos, B., Ballard, D.W., Bonhlein, E., Siekevitz, M. and Greene, W.C., Science, 244 (1989) 457.
Shibuya, H., Yoneyama, M. and Taniguchi, T., Int. Immunol., 1 (1989) 43.
Briegel, K., Hentsch, B., Pfeuffer, I. and Serffing, E., Nucleic Acids Res., 19 (1991) 5929.
Frantz, B., Nordby, E.C., Bren, G., Steffan, N., Paya, C.V., Kincaid, R.L., Tocci, M.J., O'Keefe, S.J. and O'Neill, E.A., EMBO J., 13 (1994) 861.
Shaw, J.P., Utz, P.J., Durand, D.B., Toole, J.J., Emmel, E.A. and Crabtree, G.R., Science, 241 (1988) 202.
Thompson, C.B., Wang, C.Y., Ho, I.C., Bohjanen, P.R., Petryniak, B., June, C.H., Miesfeldt, S., Zhang, L., Nabel, G.J., Karpinski, B. and Leiden, J.M., Mol. Cell. Biol., 12 (1992) 1043.
Ullman, K.S., Northrop, J.P., Admon, A. and Crabtree, G.R., Genes Dev., 7 (1993) 188.
Altmeyer, A., Staruch, M., Fischer, P.A., Durette, P.L., Tocci, M.J., Sigal, N.H. and Dumont, F.J., Int. J. Immunopharmacol., 13 (1991) 1187.
Jain, J., Valge, A.V. and Rao, A., J. Immunol., 148 (1992) 1240.
Jain, J., McCaffrey, P.G., Valge, A.V. and Rao, A., Nature, 356 (1992) 801.
Flanagan, W.M., Corthesy, B., Bram, R.J. and Crabtree, G.R., Nature, 352 (1991) 803.
Northrop, J.P., Ullman, K.S. and Crabtree, G.R., J. Biol. Chem., 268 (1993) 2917.
McCaffrey, P.G., Perrino, B.A., Soderling, T.R. and Rao, A., J. Biol. Chem., 268 (1993) 3747.
McCaffrey, P.G., Luo, C., Kerppola, T.K., Jain, J., Badalian, T.M., Ho, A.M., Burgeon, E., Lane, W.S., Lambert, J.N., Curran, T., Verdine, G.L., Rao, A. and Hogan, P.G., Science, 262 (1993) 750.
Jain, J., Miner, Z. and Rao, A., J. Immunol., 151 (1993) 837.
Jain, J.N., McCaffrey, P.G., Miner, Z., Kerppola, T.K., Lambert, J.N., Verdine, G.L., Curran, T. and Rao, A., Nature, 365 (1993) 352.
Boise, L.H., Petryniak, B., Mao, X., June, C.H., Wang, C.Y., Lindsten, T., Bravo, R., Kovary, K., Leiden, J.M. and Thompson, C.B., Mol. Cell. Biol., 13 (1993) 1911.
Fletcher, C., Heintz, N.H. and Roeder, R.G., Cell, 51 (1987) 773.
Sturm, R., Baumruker, T., Franza Jr., B.R. and Herr, W., Genes Dev., 1 (1987) 1147.
Janson, L. and Petterson, U., Proc. Natl. Acad. Sci. USA, 87 (1990) 4732.
Kristie, T.M., LeBowitz, J.H. and Sharp, P.A., EMBO J., 8 (1989) 4229.
Baeuerle, P.A., Biochim. Biophys. Acta, 1072 (1991) 63.
Blank, V., Kourilsky, P. and Israel, A., Trends Biochem. Sci., 17 (1992) 135.
Nabel, G.J. and Verma, I.M., Genes Dev., 7 (1993) 2063.
Beg, A.A. and Baldwin, A.S., Genes Dev., 7 (1993) 2064.
Baeuerle, P.A. and Baltimore, D., Cell, 53 (1988) 211.
Baeuerle, P.A. and Baltimore, D., Science, 242 (1988) 540.
Kerr, L.D., Inoue, J.-I., Davis, N., Link, E., Baeuerle, P.A., Bose, H.R. and Verma, I.M., Genes Dev., 5 (1991) 1464.
Shirakawa, F. and Mizel, S.B., Mol. Cell. Biol., 9 (1989) 2424.
Link, E., Kerr, L.D., Schreck, R., Zabel, U., Verma, I. and Baeuerle, P.A., J. Biol. Chem., 267 (1992) 239.
Muegge, K., Williams, T.M., Kant, J., Karin, M., Chiu, R., Schmidt, A., Siebenlist, U., Young, H.A. and Durum, S.K., Science, 246 (1989) 249.
Brunvand, M.W., Krumm, A. and Groudine, M., Nucleic Acids Res., 21 (1993) 4824.
Boyle, W.J., Smeal, T., Defize, L.H., Angel, P., Woodgett, J.R., Karin, M. and Hunter, T., Cell, 64 (1991) 573.
Smeal, T., Binetruy, B., Mercola, D., Grover, B.A., Heidecker, G., Rapp, U.R. and Karin, M., Mol. Cell. Biol., 12 (1992) 3507.
Smeal, T., Binetruy, B., Mercola, D.A., Birrer, M. and Karin, M., Nature, 354 (1991) 494.
Binetruy, B., Smeal, T. and Karin, M., Nature, 351 (1991) 122.
Handschumacher, R.E., Harding, M.W., Rice, J., Drugge, R.J. and Speicher, D.W., Science, 226 (1984) 544.
Harding, M.W., Handschumacher, R.E. and Speicher, D.W., J. Biol. Chem., 261 (1986) 8547.
Koletsky, A.J., Harding, M.W. and Handschumacher, R.E., J. Immunol., 137 (1986) 1054.
Siekierka, J.J., Hung, S.H., Poe, M., Lin, C.S. and Sigal, N.H., Nature, 341 (1989) 755.
Harding, M.W., Galat, A., Uehling, D.E. and Schreiber, S.L., Nature, 341 (1989) 758.
Siekierka, J.J., Wiederrecht, G., Greulich, H., Boulton, D., Hung, S.H., Cryan, J., Hodges, P.J. and Sigal, N.H., J. Biol. Chem., 265 (1990) 21011.
Takahashi, N., Hayano, T. and Suzuki, M., Nature, 337 (1989) 473.
Fischer, G., Wittmann, L.B., Lang, K., Kiefhaber, T. and Schmid, F.X., Nature, 337 (1989) 476.
Bierer, B.E., Somers, P.K., Wandless, T.J., Burakoff, S.J. and Schreiber, S.L., Science, 250 (1990) 556.
Dumont, F.J., Staruch, M.J., Koprak, S.L., Siekierka, J.J., Lin, C.S., Harrison, R., Sewell, T., Kindt, V.M., Beattie, T.R., Wyvratt, M. and Sigal, N.H., J. Exp. Med., 176 (1992) 751.
Dumont, F.J., Melino, M.R., Staruch, M.J., Koprak, S.L., Fischer, P.A. and Sigal, N.H., J. Immunol., 144 (1990) 1418.
Liu, J., Farmer, J.J., Lane, W.S., Friedman, J., Weissman, I. and Schreiber, S.L., Cell, 66 (1991) 807.
Wallace, R.W., Lynch, T.J., Tallant, E.A. and Cheung, W.Y., J. Biol. Chem., 254 (1979) 377.
Klee, C.B. and Krinks, M.H., Biochemistry, 17 (1978) 120.
Sharma, R.K., Desai, R., Waisman, D.M. and Wang, J.H., J. Biol. Chem., 254 (1979) 4276.
Klee, C.B., Crouch, T.H. and Krinks, M.H., Proc. Natl. Acad. Sci. USA, 79 (1979) 6270.
Klee, C.B. and Haiech, J., Ann. New York Acad. Sci., 356 (1980) 43.
Yang, S.-D., Tallant, E.A. and Cheung, W.Y., Biochem. Biophys. Res. Commun., 106 (1982) 1419.
Stewart, A.A., Ingebritsen, T.S., Manalan, A., Klee, C.B. and Cohen, P., FEBS Lett., 137 (1982) 80.
Ingebritsen, T.S., Stewart, A.A. and Cohen, P., Eur. J. Biochem., 132 (1983) 297.
Kincaid, R., Adv. Sec. Mess. Phosphoprotein Res., 27 (1993) 1.
Persechini, A., Moncrief, N.D. and Kretsinger, R.H., Trends Neurosci., 12 (1989) 462.
Aitken, A., Cohen, P., Santikarn, S., Williams, D.H., Calder, A.G., Smith, A. and Klee, C.B., FEBS Lett., 150 (1982) 314.
Ueki, K. and Kincaid, R.L., J. Biol. Chem., 268 (1993) 6554.
Merat, D.L., Hu, Z.Y., Carter, T.E. and Cheung, W.Y., J. Biol. Chem., 260 (1985) 11053.
King, M.M. and Huang, C.Y., J. Biol. Chem., 259 (1984) 8847.
Vincent, J.B. and Averill, B.A., FEBS Lett., 263 (1990) 265.
King, M.M. and Huang, C.Y., Biochem. Biophys. Res. Commun., 114 (1983) 955.
Pallen, C.J. and Wang, J.H., J. Biol. Chem., 259 (1984) 6134.
Yokoyama, N. and Wang, J.H., FEBS Lett., 337 (1994) 128.
Hubbard, M.J. and Klee, C.B., Biochemistry, 28 (1989) 1868.
Manalan, A.S. and Klee, C.B., Proc. Natl. Acad. Sci. USA, 80 (1983) 4291.
Tallant, E.A. and Cheung, W.Y., Biochemistry, 23 (1984) 973.
O'Keefe, S.J., Tamura, J., Kincaid, R.L., Tocci, M.J. and O'Neill, E.A., Nature, 357 (1992) 692.
Wallace, R.W., Tallant, E.A. and McManus, M.C., Biochemistry, 26 (1987) 2766.
Donelladeana, A., Krinks, M.H., Ruzzene, M., Klee, C. and Pinna, L.A., Eur. J. Biochem., 219 (1994) 109.
Billingsley, M.L., Pennypacker, K.R., Hoover, C.G., Brigati, D.J. and Kincaid, R.L., Proc. Natl. Acad. Sci. USA, 82 (1985) 7585.
Guerini, D. and Klee, C.B., Proc. Natl. Acad. Sci. USA, 86 (1989) 9183.
Kincaid, R.L., Nightingale, M.S. and Martin, B.M., Proc. Natl. Acad. Sci. USA, 85 (1988) 8983.
Kincaid, R.L., Giri, P.R., Higuchi, S., Tamura, J., Dixon, S.C., Marietta, C.A., Amorese, D.A. and Martin, B.M., J. Biol. Chem., 265 (1990) 11312.
Muramatsu, T. and Kincaid, R.L., Biochim. Biophys. Acta, 1178 (1993) 117.
Muramatsu, T., Giri, P.R., Higuchi, S. and Kincaid, R.L., Proc. Natl. Acad. Sci. USA, 89 (1992) 529.
Giri, P.R., Marietta, C.A., Higuchi, S. and Kincaid, R.L., DNA Cell Biol., 11 (1992) 415.
Ueki, K., Muramatsu, T. and Kincaid, R.L., Biochem. Biophys. Res. Commun., 187 (1992) 537.
Sugimoto, M., Matsui, H., Etoh, S., Shimizu, T., Nishio, H., Moia, L.J., Tokuda, M., Itano, T., Takenaka, I. and Hatase, O., Biochem. Biophys. Res. Commun., 180 (1991) 1476.
Kincaid, R.L., Takayama, H., Billingsley, M.L. and Sitkovsky, M.V., Nature, 330 (1987) 176.
Fruman, D.A., Klee, C.B., Bierer, B.E. and Burakoff, S.J., Proc. Natl. Acad. Sci. USA, 89 (1992) 3686.
Clipstone, N.A. and Crabtree, G.R., Nature, 357 (1992) 695.
Moll, T., Tebb, G., Surana, U., Robitsch, H. and Nasmyth, K., Cell, 66 (1991) 743.
Ghosh, S. and Baltimore, D., Nature, 344 (1990) 678.
Minshull, J., BioEssays, 15 (1993) 149.
Goldfeld, A.E., Flemington, E.K., Boussiotis, V.A., Theodos, C.M., Titus, R.G., Strominger, J.L. and Speck, S.H., Proc. Natl. Acad. Sci. USA, 89 (1992) 12198.
Schwaninger, M., Blume, R., Oetjen, E., Lux, G. and Knepel, W., J. Biol. Chem., 268 (1993) 23111.
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O'Keefe, S.J., O'Neill, E.A. Cyclosporin A and FK-506: Immunosuppression, inhibition of transcription and the role of calcineurin. Perspectives in Drug Discovery and Design 2, 85–102 (1994). https://doi.org/10.1007/BF02171738
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DOI: https://doi.org/10.1007/BF02171738