0 10 Activation Activation NNP 11 13 of of IN 14 22 NF-kappa NF-kappa NNP 23 24 B B NNP 25 27 in in FW 28 32 vivo vivo FW 33 35 is be VBZ 36 45 regulated regulate VBN 46 48 by by IN 49 57 multiple multiple JJ 58 74 phosphorylations phosphorylation NNS 74 75 . . . 77 80 The the DT 81 91 activation activation NN 92 94 of of IN 95 102 nuclear nuclear JJ 103 109 factor factor NN 110 115 kappa kappa NN 116 117 B B NNP 118 119 ( ( ( 119 127 NF-kappa NF-kappa NNP 128 129 B B NNP 129 130 ) ) ) 131 133 in in IN 134 140 intact intact JJ 141 146 cells cell NNS 147 149 is be VBZ 150 165 mechanistically mechanistically RB 166 169 not not RB 170 174 well well RB 175 185 understood understand VBN 185 186 . . . 187 196 Therefore therefore RB 197 199 we we PRP 200 212 investigated investigate VBD 213 216 the the DT 217 230 modifications modification NNS 231 238 imposed impose VBN 239 241 on on IN 242 250 NF-kappa NF-kappa NNP 251 254 B/I B/I NNP 255 260 kappa kappa NN 261 262 B B NNP 263 273 components component NNS 274 283 following follow VBG 284 295 stimulation stimulation NN 296 299 and and CC 300 304 show show VBP 305 309 that that IN 310 313 the the DT 314 319 final final JJ 320 324 step step NN 325 327 of of IN 328 336 NF-kappa NF-kappa NNP 337 338 B B NNP 339 348 induction induction NN 349 351 in in FW 352 356 vivo vivo FW 357 365 involves involve VBZ 366 381 phosphorylation phosphorylation NN 382 384 of of IN 385 392 several several JJ 393 400 members member NNS 401 403 of of IN 404 407 the the DT 408 416 NF-kappa NF-kappa NNP 417 420 B/I B/I NNP 421 426 kappa kappa NN 427 428 B B NNP 429 436 protein protein NN 437 445 families family NNS 445 446 . . . 447 449 In in IN 450 454 HeLa HeLa NNP 455 460 cells cell NNS 461 463 as as RB 464 468 well well RB 469 471 as as IN 472 474 in in IN 475 476 B B NNP 477 482 cells cell NNS 482 483 , , , 484 493 TNF-alpha TNF-alpha NNP 494 501 rapidly rapidly RB 502 509 induced induce VBD 510 517 nuclear nuclear JJ 518 531 translocation translocation NN 532 541 primarily primarily RB 542 544 of of IN 545 552 p50-p65 p50-p65 NN 552 553 , , , 554 557 but but CC 558 561 not not RB 562 564 of of IN 565 570 c-rel c-rel NN 570 571 . . . 572 576 Both both CC 577 585 NF-kappa NF-kappa NNP 586 587 B B NNP 588 598 precursors precursor NNS 599 602 and and CC 603 604 I i NN 605 610 kappa kappa NN 611 612 B B NNP 613 618 alpha alpha NN 619 625 became become VBD 626 634 strongly strongly RB 635 649 phosphorylated phosphorylate VBN 650 654 with with IN 655 658 the the DT 659 663 same same JJ 664 672 kinetics kinetic NNS 672 673 . . . 674 676 In in IN 677 685 addition addition NN 686 688 to to TO 689 692 the the DT 693 702 inducible inducible JJ 703 718 phosphorylation phosphorylation NN 719 724 after after IN 725 736 stimulation stimulation NN 736 737 , , , 738 739 B B NNP 740 751 lymphocytes lymphocyte NNS 752 762 containing contain VBG 763 775 constitutive constitutive JJ 776 783 nuclear nuclear JJ 784 792 NF-kappa NF-kappa NNP 793 794 B B NNP 795 803 revealed reveal VBD 804 818 constitutively constitutively RB 819 833 phosphorylated phosphorylate VBN 834 837 p65 p65 NN 838 841 and and CC 842 843 I i NN 844 849 kappa kappa NN 850 851 B B NNP 852 857 alpha alpha NN 857 858 . . . 859 874 Phosphorylation Phosphorylation NNP 875 878 was be VBD 879 890 accompanied accompany VBN 891 893 by by IN 894 901 induced induce VBN 902 912 processing processing NN 913 915 of of IN 916 919 the the DT 920 930 precursors precursor NNS 931 935 p100 p100 NN 936 939 and and CC 940 944 p105 p105 NN 945 948 and and CC 949 951 by by IN 952 963 degradation degradation NN 964 966 of of IN 967 968 I i NN 969 974 kappa kappa NN 975 976 B B NNP 977 982 alpha alpha NN 982 983 . . . 984 986 As as IN 987 989 an an DT 990 992 in in FW 993 998 vitro vitro FW 999 1004 model model NN 1005 1007 we we PRP 1008 1012 show show VBP 1013 1017 that that IN 1018 1033 phosphorylation phosphorylation NN 1034 1036 of of IN 1037 1041 p105 p105 NN 1042 1049 impedes impede VBZ 1050 1053 its its PRP$ 1054 1061 ability ability NN 1062 1064 to to TO 1065 1073 interact interact VB 1074 1078 with with IN 1079 1087 NF-kappa NF-kappa NNP 1088 1089 B B NNP 1089 1090 , , , 1091 1093 as as IN 1094 1097 has have VBZ 1098 1102 been be VBN 1103 1108 shown show VBN 1109 1115 before before IN 1116 1119 for for IN 1120 1121 I i NN 1122 1127 kappa kappa NN 1128 1129 B B NNP 1130 1135 alpha alpha NN 1135 1136 . . . 1137 1149 Surprisingly surprisingly RB 1149 1150 , , , 1151 1155 even even RB 1156 1159 p65 p65 NN 1159 1160 , , , 1161 1164 but but CC 1165 1168 not not RB 1169 1174 c-rel c-rel NN 1174 1175 , , , 1176 1179 was be VBD 1180 1194 phosphorylated phosphorylate VBN 1195 1200 after after IN 1201 1210 induction induction NN 1211 1213 in in FW 1214 1218 vivo vivo FW 1218 1219 , , , 1220 1230 suggesting suggest VBG 1231 1235 that that IN 1236 1245 TNF-alpha TNF-alpha NNP 1246 1257 selectively selectively RB 1258 1267 activates activate VBZ 1268 1272 only only RB 1273 1281 specific specific JJ 1282 1290 NF-kappa NF-kappa NNP 1291 1292 B B NNP 1293 1303 heteromers heteromer NNS 1304 1307 and and CC 1308 1312 that that IN 1313 1326 modifications modification NNS 1327 1335 regulate regulate VBP 1336 1339 not not RB 1340 1344 only only RB 1345 1346 I i NN 1347 1352 kappa kappa NN 1353 1354 B B NNP 1355 1364 molecules molecule NNS 1365 1368 but but CC 1369 1373 also also RB 1374 1382 NF-kappa NF-kappa NNP 1383 1384 B B NNP 1385 1394 molecules molecule NNS 1394 1395 . . . 1396 1398 In in IN 1399 1403 fact fact NN 1403 1404 , , , 1405 1413 cellular cellular JJ 1414 1422 NF-kappa NF-kappa NNP 1423 1424 B B NNP 1425 1433 activity activity NN 1434 1437 was be VBD 1438 1463 phosphorylation-dependent phosphorylation-dependent JJ 1464 1467 and and CC 1468 1471 the the DT 1472 1475 DNA dna NN 1476 1483 binding binding NN 1484 1492 activity activity NN 1493 1495 of of IN 1496 1510 p65-containing p65-containing JJ 1511 1519 NF-kappa NF-kappa NNP 1520 1521 B B NNP 1522 1525 was be VBD 1526 1534 enhanced enhance VBN 1535 1537 by by IN 1538 1553 phosphorylation phosphorylation NN 1554 1556 in in FW 1557 1562 vitro vitro FW 1562 1563 . . . 1564 1575 Furthermore furthermore RB 1575 1576 , , , 1577 1579 we we PRP 1580 1585 found find VBD 1586 1590 that that IN 1591 1594 the the DT 1595 1604 induction induction NN 1605 1607 by by IN 1608 1616 hydrogen hydrogen NN 1617 1625 peroxide peroxide NN 1626 1628 of of IN 1629 1637 NF-kappa NF-kappa NNP 1638 1639 B B NNP 1640 1653 translocation translocation NN 1654 1656 to to TO 1657 1660 the the DT 1661 1668 nucleus nucleus NN 1668 1669 , , , 1670 1675 which which WDT 1676 1678 is be VBZ 1679 1686 assumed assume VBN 1687 1689 to to TO 1690 1692 be be VB 1693 1702 triggered trigger VBN 1703 1705 by by IN 1706 1714 reactive reactive JJ 1715 1721 oxygen oxygen NN 1722 1735 intermediates intermediate NNS 1735 1736 , , , 1737 1741 also also RB 1742 1751 coincided coincide VBD 1752 1756 with with IN 1757 1770 incorporation incorporation NN 1771 1773 of of IN 1774 1783 phosphate phosphate NN 1784 1788 into into IN 1789 1792 the the DT 1793 1797 same same JJ 1798 1806 subunits subunit NNS 1807 1811 that that WDT 1812 1816 were be VBD 1817 1825 modified modify VBN 1826 1831 after after IN 1832 1843 stimulation stimulation NN 1844 1846 by by IN 1847 1856 TNF-alpha TNF-alpha NNP 1856 1857 . . . 1858 1862 Thus thus RB 1862 1863 , , , 1864 1879 phosphorylation phosphorylation NN 1880 1887 appears appear VBZ 1888 1890 to to TO 1891 1893 be be VB 1894 1895 a a DT 1896 1903 general general JJ 1904 1913 mechanism mechanism NN 1914 1917 for for IN 1918 1928 activation activation NN 1929 1931 of of IN 1932 1940 NF-kappa NF-kappa NNP 1941 1942 B B NNP 1943 1945 in in FW 1946 1950 vivo vivo FW 1950 1951 . . .