0 3 The the DT 4 8 role role NN 9 11 of of IN 12 17 NFATp NFATp NNP 18 20 in in IN 21 32 cyclosporin cyclosporin NN 33 44 A-sensitive a-sensitive JJ 45 50 tumor tumor NN 51 59 necrosis necrosis NN 60 72 factor-alpha factor-alpha NN 73 77 gene gene NN 78 91 transcription transcription NN 91 92 . . . 94 97 The the DT 98 103 tumor tumor NN 104 112 necrosis necrosis NN 113 125 factor-alpha factor-alpha NN 126 127 ( ( ( 127 130 TNF TNF NNP 131 136 alpha alpha NN 136 137 ) ) ) 138 142 gene gene NN 143 145 is be VBZ 146 148 an an DT 149 158 immediate immediate JJ 159 164 early early JJ 165 169 gene gene NN 170 172 in in IN 173 182 activated activate VBN 183 184 T t NN 185 190 cells cell NNS 190 191 , , , 192 194 in in IN 195 199 that that IN 200 202 it it PRP 203 205 is be VBZ 206 213 rapidly rapidly RB 214 221 induced induce VBN 222 229 without without IN 230 231 a a DT 232 243 requirement requirement NN 244 247 for for IN 248 255 protein protein NN 256 265 synthesis synthesis NN 265 266 . . . 267 274 Maximal maximal JJ 275 284 induction induction NN 285 287 of of IN 288 291 TNF TNF NNP 292 297 alpha alpha NN 298 302 mRNA mRNA NNP 303 306 can can MD 307 309 be be VB 310 317 induced induce VBN 318 320 by by IN 321 330 treatment treatment NN 331 333 of of IN 334 335 T t NN 336 341 cells cell NNS 342 346 with with IN 347 354 calcium calcium NN 355 365 ionophores ionophore NNS 366 371 alone alone RB 371 372 , , , 373 376 via via IN 377 378 a a DT 379 400 calcineurin-dependent calcineurin-dependent JJ 401 408 process process NN 409 413 that that WDT 414 416 is be VBZ 417 424 blocked block VBN 425 427 by by IN 428 439 cyclosporin cyclosporin NN 440 441 A a NN 441 442 . . . 443 445 We we PRP 446 450 have have VBP 451 461 previously previously RB 462 472 identified identify VBN 473 474 a a DT 475 483 promoter promoter NN 484 491 element element NN 491 492 , , , 493 498 kappa kappa NN 499 500 3 3 CD 500 501 , , , 502 506 that that WDT 507 509 is be VBZ 510 518 required require VBN 519 522 for for IN 523 541 calcium-stimulated calcium-stimulated JJ 541 542 , , , 543 554 cyclosporin cyclosporin NN 555 566 A-sensitive a-sensitive JJ 567 576 induction induction NN 577 579 of of IN 580 583 the the DT 584 587 TNF TNF NNP 588 593 alpha alpha NN 594 598 gene gene NN 599 601 in in IN 602 611 activated activate VBN 612 613 T t NN 614 619 cells cell NNS 619 620 . . . 621 625 Here here RB 625 626 , , , 627 629 we we PRP 630 641 demonstrate demonstrate VBP 642 646 that that IN 647 650 the the DT 651 656 kappa kappa NN 657 658 3 3 CD 659 666 binding binding NN 667 673 factor factor NN 674 682 contains contain VBZ 683 688 NFATp NFATp NNP 688 689 , , , 690 691 a a DT 692 713 cyclosporin-sensitive cyclosporin-sensitive JJ 714 725 DNA-binding dna-binding JJ 726 733 protein protein NN 734 742 required require VBN 743 746 for for IN 747 760 interleukin-2 interleukin-2 NN 761 765 gene gene NN 766 779 transcription transcription NN 779 780 . . . 781 786 NFATp NFATp NNP 787 792 binds bind VBZ 793 795 to to TO 796 799 two two CD 800 805 sites site NNS 806 812 within within IN 813 816 the the DT 817 822 kappa kappa NN 823 824 3 3 CD 825 832 element element NN 832 833 , , , 834 837 and and CC 838 847 occupancy occupancy NN 848 850 of of IN 851 855 both both DT 856 861 sites site NNS 862 864 is be VBZ 865 873 required require VBN 874 877 for for IN 878 881 TNF TNF NNP 882 887 alpha alpha NN 888 892 gene gene NN 893 902 induction induction NN 902 903 . . . 904 908 Thus thus RB 908 909 , , , 910 918 although although IN 919 922 the the DT 923 928 kappa kappa NN 929 930 3 3 CD 931 938 element element NN 939 942 has have VBZ 943 949 little little JJ 950 958 sequence sequence NN 959 969 similarity similarity NN 970 972 to to TO 973 978 other other JJ 979 992 NFATp-binding nfatp-binding JJ 993 998 sites site NNS 998 999 , , , 1000 1002 it it PRP 1003 1010 appears appear VBZ 1011 1013 to to TO 1014 1022 function function VB 1023 1025 as as IN 1026 1027 a a DT 1028 1049 cyclosporin-sensitive cyclosporin-sensitive JJ 1050 1058 promoter promoter NN 1059 1066 element element NN 1067 1069 in in IN 1070 1071 T t NN 1072 1077 cells cell NNS 1078 1080 by by IN 1081 1087 virtue virtue NN 1088 1090 of of IN 1091 1094 its its PRP$ 1095 1102 ability ability NN 1103 1105 to to TO 1106 1110 bind bind VB 1111 1116 NFATp nfatp NN 1116 1117 . . . 1118 1121 The the DT 1122 1133 involvement involvement NN 1134 1136 of of IN 1137 1142 NFATp NFATp NNP 1143 1145 in in IN 1146 1161 transcriptional transcriptional JJ 1162 1172 activation activation NN 1173 1175 of of IN 1176 1180 both both CC 1181 1184 the the DT 1185 1198 interleukin-2 interleukin-2 NN 1199 1202 and and CC 1203 1206 TNF tnf NN 1207 1212 alpha alpha NN 1213 1218 genes gene NNS 1219 1227 suggests suggest VBZ 1228 1232 that that IN 1233 1237 this this DT 1238 1244 factor factor NN 1245 1250 plays play VBZ 1251 1253 an an DT 1254 1263 important important JJ 1264 1268 role role NN 1269 1271 in in IN 1272 1275 the the DT 1276 1286 coordinate coordinate JJ 1287 1296 induction induction NN 1297 1299 of of IN 1300 1308 multiple multiple JJ 1309 1317 cytokine cytokine NN 1318 1323 genes gene NNS 1323 1324 , , , 1325 1333 starting start VBG 1334 1336 at at IN 1337 1340 the the DT 1341 1349 earliest early JJS 1350 1356 stages stage NNS 1357 1359 of of IN 1360 1361 T t NN 1362 1366 cell cell NN 1367 1377 activation activation NN 1377 1378 . . .