0 11 Calcineurin Calcineurin NNP 12 16 acts act VBZ 17 19 in in IN 20 27 synergy synergy NN 28 32 with with IN 33 36 PMA PMA NNP 37 39 to to TO 40 50 inactivate inactivate VB 51 52 I i NN 53 58 kappa kappa NN 59 65 B/MAD3 b/mad3 NN 65 66 , , , 67 69 an an DT 70 79 inhibitor inhibitor NN 80 82 of of IN 83 91 NF-kappa NF-kappa NNP 92 94 B. B. NNP 96 99 The the DT 100 113 interleukin-2 interleukin-2 NN 114 115 ( ( ( 115 119 IL-2 il-2 NN 119 120 ) ) ) 121 129 promoter promoter NN 130 138 consists consist VBZ 139 141 of of IN 142 149 several several JJ 150 161 independent independent JJ 162 163 T t NN 164 168 cell cell NN 169 177 receptor receptor NN 178 179 ( ( ( 179 182 TcR TcR NNP 182 183 ) ) ) 184 194 responsive responsive JJ 195 203 elements element NNS 203 204 . . . 205 208 The the DT 209 218 induction induction NN 219 221 of of IN 222 231 promoters promoter NNS 232 241 dependent dependent JJ 242 244 on on IN 245 250 these these DT 251 259 elements element NNS 260 262 is be VBZ 263 274 inhibitable inhibitable JJ 275 277 by by IN 278 281 the the DT 282 300 immunosuppressants immunosuppressant NNS 301 312 cyclosporin cyclosporin NN 313 314 A a NN 315 316 ( ( ( 316 319 CsA CsA NNP 319 320 ) ) ) 321 324 and and CC 325 335 tacrolimus tacrolimus NN 336 337 ( ( ( 337 343 FK-506 FK-506 NNP 343 344 ) ) ) 344 345 . . . 346 357 Calcineurin Calcineurin NNP 357 358 , , , 359 360 a a DT 361 386 Ca2+/calmodulin-dependent ca2+/calmodulin-dependent JJ 387 394 protein protein NN 395 406 phosphatase phosphatase NN 406 407 , , , 408 410 is be VBZ 411 414 the the DT 415 422 FK-506- fk-506- NN 423 426 and and CC 427 440 CsA-sensitive csa-sensitive JJ 441 447 enzyme enzyme NN 448 456 required require VBN 457 460 for for IN 461 464 TcR TcR NNP 465 473 mediated mediated JJ 474 484 activation activation NN 485 487 of of IN 488 491 the the DT 492 496 IL-2 il-2 NN 497 505 promoter promoter NN 505 506 . . . 507 509 We we PRP 510 516 report report VBP 517 521 that that IN 522 523 a a DT 524 538 constitutively constitutively RB 539 545 active active JJ 546 550 form form NN 551 553 of of IN 554 565 calcineurin calcineurin NN 566 575 partially partially RB 576 587 substitutes substitute VBZ 588 591 for for IN 592 595 the the DT 596 600 Ca2+ ca2+ NN 601 612 co-stimulus co-stimulus NN 613 621 required require VBN 622 624 to to TO 625 633 activate activate VB 634 637 the the DT 638 642 IL-2 il-2 NN 643 651 promoter promoter NN 652 660 elements element NNS 661 666 IL-2A il-2a NN 667 668 ( ( ( 668 673 which which WDT 674 679 binds bind VBZ 680 683 the the DT 684 691 factors factor NNS 692 695 OAP OAP NNP 696 699 and and CC 700 705 Oct-1 Oct-1 NNP 705 706 ) ) ) 707 710 and and CC 711 716 IL-2E IL-2E NNP 717 718 ( ( ( 718 723 which which WDT 724 729 binds bind VBZ 730 735 NF-AT NF-AT NNP 735 736 ) ) ) 736 737 , , , 738 741 and and CC 742 752 completely completely RB 753 764 substitutes substitute VBZ 765 768 for for IN 769 772 the the DT 773 777 Ca2+ ca2+ NN 778 789 co-stimulus co-stimulus NN 790 798 required require VBN 799 801 to to TO 802 811 stimulate stimulate VB 812 814 an an DT 815 823 NF-kappa NF-kappa NNP 824 835 B-dependent b-dependent JJ 836 843 element element NN 843 844 . . . 845 856 Calcineurin Calcineurin NNP 857 867 stimulates stimulate VBZ 868 871 the the DT 872 880 NF-kappa NF-kappa NNP 881 882 B B NNP 883 890 element element NN 891 893 by by IN 894 903 enhancing enhance VBG 904 916 inactivation inactivation NN 917 919 of of IN 920 921 I i NN 922 927 kappa kappa NN 928 934 B/MAD3 b/mad3 NN 934 935 , , , 936 938 an an DT 939 948 inhibitor inhibitor NN 949 951 of of IN 952 960 NF-kappa NF-kappa NNP 961 962 B B NNP 962 963 , , , 964 971 thereby thereby RB 972 982 increasing increase VBG 983 986 the the DT 987 993 amount amount NN 994 996 of of IN 997 1004 nuclear nuclear JJ 1005 1013 NF-kappa NF-kappa NNP 1014 1015 B B NNP 1016 1019 DNA DNA NNP 1020 1027 binding binding NN 1028 1036 activity activity NN 1036 1037 . . . 1038 1043 These these DT 1044 1048 data datum NNS 1049 1056 provide provide VBP 1057 1060 the the DT 1061 1066 first first JJ 1067 1080 demonstration demonstration NN 1081 1083 in in FW 1084 1088 vivo vivo FW 1089 1093 that that IN 1094 1104 activation activation NN 1105 1107 of of IN 1108 1109 a a DT 1110 1117 protein protein NN 1118 1129 phosphatase phosphatase NN 1130 1133 can can MD 1134 1144 inactivate inactivate VB 1145 1146 I i NN 1147 1152 kappa kappa NN 1153 1154 B B NNP 1154 1155 , , , 1156 1159 and and CC 1160 1167 suggest suggest VBP 1168 1171 one one CD 1172 1180 possible possible JJ 1181 1192 explanation explanation NN 1193 1196 for for IN 1197 1212 mechanism-based mechanism-based JJ 1213 1223 toxicities toxicity NNS 1224 1234 associated associate VBN 1235 1239 with with IN 1240 1246 FK-506 FK-506 NNP 1247 1250 and and CC 1251 1254 CsA CsA NNP 1255 1257 by by IN 1258 1271 demonstrating demonstrate VBG 1272 1276 that that IN 1277 1282 these these DT 1283 1288 drugs drug NNS 1289 1292 can can MD 1293 1300 inhibit inhibit VB 1301 1304 the the DT 1305 1326 calcineurin-dependent calcineurin-dependent JJ 1327 1337 activation activation NN 1338 1340 of of IN 1341 1342 a a DT 1343 1352 virtually virtually RB 1353 1363 ubiquitous ubiquitous JJ 1364 1377 transcription transcription NN 1378 1384 factor factor NN 1384 1385 . . .