0 8 Biphasic biphasic JJ 9 16 control control NN 17 19 of of IN 20 27 nuclear nuclear JJ 28 40 factor-kappa factor-kappa NN 41 42 B B NNP 43 53 activation activation NN 54 56 by by IN 57 60 the the DT 61 62 T t NN 63 67 cell cell NN 68 76 receptor receptor NN 77 84 complex complex NN 84 85 : : : 86 90 role role NN 91 93 of of IN 94 99 tumor tumor NN 100 108 necrosis necrosis NN 109 115 factor factor NN 116 121 alpha alpha NN 121 122 . . . 124 127 The the DT 128 138 regulation regulation NN 139 141 of of IN 142 149 nuclear nuclear JJ 150 156 factor factor NN 157 158 ( ( ( 158 167 NF)-kappa NF)-kappa NNP 168 169 B B NNP 170 180 activation activation NN 181 183 by by IN 184 187 the the DT 188 189 T t NN 190 194 cell cell NN 195 203 receptor receptor NN 204 205 ( ( ( 205 213 TcR)/CD3 tcr)/cd3 NN 214 221 complex complex NN 222 224 in in IN 225 232 primary primary JJ 233 238 human human JJ 239 240 T t NN 241 246 cells cell NNS 247 250 has have VBZ 251 255 been be VBN 256 263 studied study VBN 264 266 at at IN 267 274 various various JJ 275 280 times time NNS 281 286 after after IN 287 297 activation activation NN 297 298 . . . 299 303 Only only RB 304 307 p50 p50 NN 308 316 NF-kappa NF-kappa NNP 317 318 B B NNP 319 326 protein protein NN 327 332 bound bind VBD 333 336 the the DT 337 342 kappa kappa NN 343 344 B B NNP 345 352 element element NN 353 355 of of IN 356 369 interleukin-2 interleukin-2 NN 370 378 receptor receptor NN 379 380 ( ( ( 380 385 IL-2R IL-2R NNP 385 386 ) ) ) 387 392 alpha alpha NN 393 398 chain chain NN 399 407 promoter promoter NN 408 410 on on IN 411 418 resting rest VBG 419 420 T t NN 421 426 cells cell NNS 426 427 . . . 428 435 However however RB 435 436 , , , 437 448 immediately immediately RB 449 454 after after IN 455 462 TcR/CD3 tcr/cd3 NN 463 476 cross-linking cross-linking NN 477 478 ( ( ( 478 483 after after IN 484 497 approximately approximately RB 498 499 1 1 CD 500 501 h h NN 501 502 ; ; : 503 512 immediate immediate JJ 512 513 ) ) ) 514 521 binding binding NN 522 524 of of IN 525 532 p50.p65 p50.p65 NN 533 545 heterodimers heterodimer NNS 546 549 was be VBD 550 559 observed. observed. VBN 560 569 p50.c-rel p50.c-rel NN 570 582 heterodimers heterodimer NNS 583 587 were be VBD 588 592 also also RB 593 601 detected detect VBN 602 607 bound bind VBN 608 610 to to TO 611 615 this this DT 616 624 sequence sequence NN 625 627 at at IN 628 633 early early JJ 634 638 time time NN 639 645 points point NNS 646 647 ( ( ( 647 651 7-16 7-16 CD 652 653 h h NN 653 654 ; ; : 655 660 early early RB 660 661 ) ) ) 661 662 , , , 663 666 and and CC 667 671 both both DT 672 680 remained remain VBD 681 687 active active JJ 688 690 at at IN 691 696 later late JJR 697 701 time time NN 702 708 points point NNS 709 710 ( ( ( 710 712 40 40 CD 713 714 h h NN 714 715 ; ; : 716 720 late late RB 720 721 ) ) ) 722 727 after after IN 728 738 activation activation NN 738 739 . . . 740 744 This this DT 745 755 regulation regulation NN 756 761 takes take VBZ 762 767 place place NN 768 774 mainly mainly RB 775 777 at at IN 778 781 the the DT 782 787 level level NN 788 790 of of IN 791 798 nuclear nuclear JJ 799 812 translocation translocation NN 813 815 of of IN 816 819 p65 p65 NN 820 823 and and CC 824 829 c-rel c-rel NN 829 830 , , , 831 833 at at IN 834 843 immediate immediate JJ 844 847 and and CC 848 853 early early JJ 854 858 time time NN 859 865 points point NNS 865 866 . . . 867 877 Activation Activation NNP 878 882 also also RB 883 890 induced induce VBD 891 896 c-rel c-rel NN 897 900 and and CC 901 909 p105/p50 p105/p50 NN 910 914 mRNA mrna NN 915 924 synthesis synthesis NN 924 925 , , , 926 929 but but CC 930 933 not not RB 934 937 p65 p65 NN 938 942 mRNA mrna NN 943 948 whose whose WP$ 949 959 expression expression NN 960 963 was be VBD 964 976 constitutive constitutive JJ 976 977 . . . 978 991 Interestingly interestingly RB 991 992 , , , 993 996 all all PDT 997 1002 those those DT 1003 1008 early early JJ 1009 1012 and and CC 1013 1017 late late JJ 1018 1024 events event NNS 1024 1025 , , , 1026 1029 but but CC 1030 1033 not not RB 1034 1037 the the DT 1038 1047 immediate immediate JJ 1048 1052 ones one NNS 1052 1053 , , , 1054 1058 were be VBD 1059 1068 inhibited inhibit VBN 1069 1071 by by IN 1072 1073 a a DT 1074 1086 neutralizing neutralize VBG 1087 1097 anti-tumor anti-tumor JJ 1098 1106 necrosis necrosis NN 1107 1113 factor factor NN 1114 1119 alpha alpha NN 1120 1121 ( ( ( 1121 1130 TNF-alpha TNF-alpha NNP 1130 1131 ) ) ) 1132 1142 monoclonal monoclonal JJ 1143 1151 antibody antibody NN 1151 1152 . . . 1153 1162 Similarly similarly RB 1162 1163 , , , 1164 1177 cycloheximide cycloheximide NN 1178 1187 prevented prevent VBD 1188 1191 the the DT 1192 1195 p65 p65 NN 1196 1199 and and CC 1200 1205 c-rel c-rel NN 1206 1219 translocation translocation NN 1220 1223 and and CC 1224 1234 consequent consequent JJ 1235 1244 formation formation NN 1245 1247 of of IN 1248 1254 active active JJ 1255 1262 binding binding NN 1263 1275 heterodimers heterodimer NNS 1275 1276 , , , 1277 1279 at at IN 1280 1285 early early JJ 1286 1289 and and CC 1290 1294 late late JJ 1295 1300 times time NNS 1300 1301 . . . 1302 1313 Cyclosporin Cyclosporin NNP 1314 1315 A A NNP 1316 1324 impaired impair VBD 1325 1328 not not RB 1329 1333 only only RB 1334 1339 early early JJ 1340 1343 and and CC 1344 1348 late late JJ 1348 1349 , , , 1350 1353 but but CC 1354 1358 also also RB 1359 1368 immediate immediate JJ 1369 1375 events event NNS 1375 1376 ; ; : 1377 1384 however however RB 1384 1385 , , , 1386 1394 addition addition NN 1395 1397 of of IN 1398 1407 TNF-alpha TNF-alpha NNP 1408 1417 prevented prevent VBD 1418 1421 all all DT 1422 1432 inhibition inhibition NN 1432 1433 . . . 1434 1439 These these DT 1440 1447 results result NNS 1448 1456 indicate indicate VBP 1457 1461 that that IN 1462 1465 the the DT 1466 1476 regulation regulation NN 1477 1479 of of IN 1480 1488 NF-kappa NF-kappa NNP 1489 1490 B B NNP 1491 1501 activation activation NN 1502 1508 during during IN 1509 1510 T t NN 1511 1515 cell cell NN 1516 1526 activation activation NN 1527 1529 by by IN 1530 1537 TcR/CD3 tcr/cd3 NN 1538 1545 signals signal NNS 1546 1548 is be VBZ 1549 1557 biphasic biphasic JJ 1557 1558 : : : 1559 1566 TcR/CD3 TcR/CD3 NNP 1567 1575 triggers trigger VBZ 1576 1579 its its PRP$ 1580 1589 immediate immediate JJ 1590 1603 translocation translocation NN 1603 1604 , , , 1605 1610 which which WDT 1611 1613 is be VBZ 1614 1623 transient transient JJ 1624 1626 if if IN 1627 1629 no no DT 1630 1639 TNF-alpha TNF-alpha NNP 1640 1642 is be VBZ 1643 1650 present present JJ 1650 1651 . . . 1652 1661 TNF-alpha TNF-alpha NNP 1661 1662 , , , 1663 1672 therefore therefore RB 1672 1673 , , , 1674 1681 emerges emerge VBZ 1682 1684 as as IN 1685 1688 the the DT 1689 1693 main main JJ 1694 1700 factor factor NN 1701 1712 responsible responsible JJ 1713 1716 for for IN 1717 1718 a a DT 1719 1725 second second JJ 1726 1731 phase phase NN 1732 1734 of of IN 1735 1743 NF-kappa NF-kappa NNP 1744 1745 B B NNP 1746 1756 regulation regulation NN 1756 1757 , , , 1758 1769 controlling control VBG 1770 1774 both both CC 1775 1788 translocation translocation NN 1789 1791 of of IN 1792 1795 p65 p65 NN 1796 1799 and and CC 1800 1805 c-rel c-rel NN 1805 1806 , , , 1807 1810 and and CC 1811 1814 new new JJ 1815 1819 mRNA mrna NN 1820 1829 synthesis synthesis NN 1830 1833 for for IN 1834 1839 c-rel c-rel NN 1840 1843 and and CC 1844 1852 p105/p50 p105/p50 NN 1852 1853 . . .