0 5 Tpl-2 tpl-2 NN 6 13 induces induce VBZ 14 18 IL-2 il-2 NN 19 29 expression expression NN 30 32 in in IN 33 39 T-cell t-cell NN 40 45 lines line NNS 46 48 by by IN 49 59 triggering trigger VBG 60 68 multiple multiple JJ 69 78 signaling signaling NN 79 87 pathways pathway NNS 88 92 that that WDT 93 101 activate activate VBP 102 106 NFAT NFAT NNP 107 110 and and CC 111 120 NF-kappaB NF-kappaB NNP 120 121 . . . 123 126 The the DT 127 132 Tpl-2 Tpl-2 NNP 133 139 kinase kinase NNP 140 149 activates activate VBZ 150 153 the the DT 154 161 nuclear nuclear JJ 162 168 factor factor NN 169 171 of of IN 172 181 activated activate VBN 182 183 T t NN 184 189 cells cell NNS 190 191 ( ( ( 191 195 NFAT NFAT NNP 195 196 ) ) ) 197 200 and and CC 201 208 induces induce VBZ 209 213 IL-2 il-2 NN 214 224 expression expression NN 225 227 in in IN 228 234 T-cell t-cell NN 235 240 lines line NNS 240 241 . . . 242 246 Here here RB 247 249 we we PRP 250 254 show show VBP 255 259 that that IN 260 263 the the DT 264 274 activation activation NN 275 277 of of IN 278 281 the the DT 282 286 IL-2 il-2 NN 287 295 promoter promoter NN 296 298 by by IN 299 304 Tpl-2 tpl-2 NN 305 307 is be VBZ 308 317 inhibited inhibit VBN 318 320 by by IN 321 327 mutant mutant JJ 328 337 signaling signal VBG 338 347 molecules molecule NNS 348 352 that that WDT 353 360 inhibit inhibit VBP 361 364 the the DT 365 382 mitogen-activated mitogen-activated JJ 383 390 protein protein NN 391 397 kinase kinase NNP 398 399 ( ( ( 399 403 MAPK MAPK NNP 403 404 ) ) ) 405 407 or or CC 408 411 the the DT 412 428 calcineurin/NFAT calcineurin/nfat NN 429 437 pathways pathway NNS 438 441 and and CC 442 444 is be VBZ 445 453 promoted promote VBN 454 456 by by IN 457 469 combinations combination NNS 470 472 of of IN 473 482 signaling signal VBG 483 492 molecules molecule NNS 493 497 that that WDT 498 506 activate activate VBP 507 512 these these DT 513 521 pathways pathway NNS 521 522 . . . 523 525 We we PRP 525 526 , , , 527 536 therefore therefore RB 536 537 , , , 538 546 conclude conclude VBP 547 551 that that IN 552 559 signals signal NNS 560 569 generated generate VBN 570 572 by by IN 573 576 the the DT 577 588 convergence convergence NN 589 591 of of IN 592 595 the the DT 596 600 MAPK MAPK NNP 601 604 and and CC 605 608 the the DT 609 625 calcineurin/NFAT calcineurin/nfat NN 626 633 pathway pathway NN 634 637 are be VBP 638 647 necessary necessary JJ 648 651 and and CC 652 662 sufficient sufficient JJ 663 666 for for IN 667 670 the the DT 671 681 activation activation NN 682 684 of of IN 685 688 the the DT 689 693 IL-2 il-2 NN 694 702 promoter promoter NN 703 705 by by IN 706 711 Tpl-2 tpl-2 NN 711 712 . . . 713 716 The the DT 717 727 activation activation NN 728 730 of of IN 731 735 both both CC 736 739 the the DT 740 744 IL-2 il-2 NN 745 753 promoter promoter NN 754 757 and and CC 758 760 an an DT 761 772 NFAT-driven nfat-driven JJ 773 780 minimal minimal JJ 781 789 promoter promoter NN 790 794 were be VBD 795 800 shown show VBN 801 803 to to TO 804 810 depend depend VB 811 813 on on IN 814 821 signals signal NNS 822 832 transduced transduce VBN 833 835 by by IN 836 840 Raf1 Raf1 NNP 840 841 . . . 842 849 However however RB 849 850 , , , 851 853 it it PRP 854 857 was be VBD 858 862 only only RB 863 866 the the DT 867 871 IL-2 il-2 NN 872 880 promoter promoter NN 881 886 whose whose WP$ 887 897 activation activation NN 898 900 by by IN 901 906 Tpl-2 tpl-2 NN 907 910 was be VBD 911 916 fully fully RB 917 924 blocked block VBN 925 927 by by IN 928 931 the the DT 932 940 dominant dominant JJ 941 949 negative negative JJ 950 956 mutant mutant JJ 957 970 MEK1S218/222A MEK1S218/222A NNP 971 974 and and CC 975 978 the the DT 979 988 MEK1/MEK2 mek1/mek2 NN 989 998 inhibitor inhibitor NN 999 1007 PD098059 pd098059 NN 1007 1008 . . . 1009 1014 Since since IN 1015 1018 the the DT 1019 1029 activation activation NN 1030 1032 of of IN 1033 1037 NFAT NFAT NNP 1038 1040 is be VBZ 1041 1055 MAPK-dependent mapk-dependent JJ 1056 1061 these these DT 1062 1070 findings finding NNS 1071 1080 suggested suggest VBD 1081 1085 that that IN 1086 1089 the the DT 1090 1100 activation activation NN 1101 1103 of of IN 1104 1108 MAPK MAPK NNP 1109 1111 by by IN 1112 1117 Tpl-2 tpl-2 NN 1118 1120 is be VBZ 1121 1127 either either CC 1128 1139 independent independent JJ 1140 1142 or or CC 1143 1147 only only RB 1148 1157 partially partially RB 1158 1167 dependent dependent JJ 1168 1170 on on IN 1171 1175 MEK1 MEK1 NNP 1176 1179 and and CC 1180 1184 MEK2 MEK2 NNP 1184 1185 . . . 1186 1188 In in IN 1189 1197 addition addition NN 1197 1198 , , , 1199 1203 they they PRP 1204 1213 suggested suggest VBD 1214 1218 that that IN 1219 1222 the the DT 1223 1233 activation activation NN 1234 1236 of of IN 1237 1240 the the DT 1241 1245 IL-2 il-2 NN 1246 1254 promoter promoter NN 1255 1257 is be VBZ 1258 1263 under under IN 1264 1267 the the DT 1268 1275 control control NN 1276 1278 of of IN 1279 1282 not not RB 1283 1287 only only RB 1288 1292 NFAT nfat NN 1293 1296 but but CC 1297 1301 also also RB 1302 1303 a a DT 1304 1310 second second JJ 1311 1317 factor factor NN 1318 1323 whose whose WP$ 1324 1334 activation activation NN 1335 1337 is be VBZ 1338 1351 MEK-dependent mek-dependent JJ 1351 1352 . . . 1353 1364 Experiments experiment NNS 1365 1367 in in IN 1368 1373 COS-1 cos-1 NN 1374 1377 and and CC 1378 1382 EL-4 el-4 NN 1383 1388 cells cell NNS 1389 1398 confirmed confirm VBD 1399 1403 both both CC 1404 1414 hypotheses hypothesis NNS 1415 1418 and and CC 1419 1427 revealed reveal VBD 1428 1432 that that IN 1433 1436 the the DT 1437 1443 second second JJ 1444 1450 factor factor NN 1451 1460 activated activate VBN 1461 1463 by by IN 1464 1469 Tpl-2 tpl-2 NN 1470 1472 is be VBZ 1473 1482 NF-kappaB NF-kappaB NNP 1482 1483 . . . 1484 1489 While while IN 1490 1493 the the DT 1494 1504 activation activation NN 1505 1507 of of IN 1508 1511 the the DT 1512 1516 IL-2 il-2 NN 1517 1525 promoter promoter NN 1526 1529 and and CC 1530 1532 an an DT 1533 1544 NFAT-driven nfat-driven JJ 1545 1552 minimal minimal JJ 1553 1561 promoter promoter NN 1562 1564 by by IN 1565 1570 Tpl-2 tpl-2 NN 1571 1574 was be VBD 1575 1580 fully fully RB 1581 1588 blocked block VBN 1589 1591 by by IN 1592 1595 the the DT 1596 1604 dominant dominant JJ 1605 1613 negative negative JJ 1614 1620 mutant mutant JJ 1621 1625 NFAT NFAT NNP 1626 1634 delta418 delta418 NN 1634 1635 , , , 1636 1638 it it PRP 1639 1642 was be VBD 1643 1647 only only RB 1648 1657 partially partially RB 1658 1665 blocked block VBN 1666 1668 by by IN 1669 1672 the the DT 1673 1684 calcineurin calcineurin NN 1685 1694 inhibitor inhibitor NN 1695 1706 cyclosporin cyclosporin NN 1707 1708 A a NN 1709 1719 suggesting suggest VBG 1720 1724 that that IN 1725 1728 the the DT 1729 1743 Tpl-2-mediated tpl-2-mediated JJ 1744 1748 NFAT NFAT NNP 1749 1759 activation activation NN 1760 1762 is be VBZ 1763 1768 under under IN 1769 1772 the the DT 1773 1780 control control NN 1781 1783 of of IN 1784 1785 a a DT 1786 1797 combination combination NN 1798 1800 of of IN 1801 1822 calcineurin-dependent calcineurin-dependent JJ 1823 1826 and and CC 1827 1838 independent independent JJ 1839 1847 pathways pathway NNS 1847 1848 . . . 1849 1853 Both both DT 1854 1862 pathways pathway NNS 1863 1867 were be VBD 1868 1873 fully fully RB 1874 1881 blocked block VBN 1882 1884 by by IN 1885 1890 Bcl-2 bcl-2 NN 1891 1893 or or CC 1894 1902 Bcl-X(L) Bcl-X(L) NNP 1902 1903 . . .