0 10 Activation Activation NNP 11 13 of of IN 14 22 NF-kappa NF-kappa NNP 23 24 B B NNP 25 27 by by IN 28 39 phosphatase phosphatase NN 40 50 inhibitors inhibitor NNS 51 59 involves involve VBZ 60 63 the the DT 64 79 phosphorylation phosphorylation NN 80 82 of of IN 83 84 I i NN 85 90 kappa kappa NN 91 92 B B NNP 93 98 alpha alpha NN 99 101 at at IN 102 113 phosphatase phosphatase NN 114 126 2A-sensitive 2a-sensitive JJ 127 132 sites site NNS 132 133 . . . 135 145 Activation Activation NNP 146 148 of of IN 149 157 NF-kappa NF-kappa NNP 158 159 B B NNP 160 162 by by IN 163 170 various various JJ 171 179 cellular cellular JJ 180 187 stimuli stimulus NNS 188 196 involves involve VBZ 197 200 the the DT 201 216 phosphorylation phosphorylation NN 217 220 and and CC 221 231 subsequent subsequent JJ 232 243 degradation degradation NN 244 246 of of IN 247 250 its its PRP$ 251 260 inhibitor inhibitor NN 260 261 , , , 262 263 I i NN 264 269 kappa kappa NN 270 271 B B NNP 272 277 alpha alpha NN 277 278 , , , 279 287 although although IN 288 291 the the DT 292 302 underlying underlie VBG 303 312 mechanism mechanism NN 313 320 remains remain VBZ 321 328 unclear unclear JJ 328 329 . . . 330 332 In in IN 333 336 the the DT 337 344 present present JJ 345 350 study study NN 350 351 , , , 352 355 the the DT 356 360 role role NN 361 363 of of IN 364 380 serine/threonine serine/threonine NN 381 393 phosphatases phosphatas NNS 394 396 in in IN 397 400 the the DT 401 411 regulation regulation NN 412 414 of of IN 415 416 I i NN 417 422 kappa kappa NN 423 424 B B NNP 425 430 alpha alpha NN 431 446 phosphorylation phosphorylation NN 447 450 was be VBD 451 463 investigated investigate VBN 463 464 . . . 465 468 Our our PRP$ 469 476 studies study NNS 477 488 demonstrate demonstrate VBP 489 493 that that IN 494 504 incubation incubation NN 505 507 of of IN 508 513 human human JJ 514 515 T t NN 516 521 cells cell NNS 522 526 with with IN 527 530 low low JJ 531 545 concentrations concentration NNS 546 547 ( ( ( 547 560 approximately approximately RB 561 564 1-5 1-5 CD 565 567 nM nm NN 567 568 ) ) ) 569 571 of of IN 572 581 calyculin calyculin NN 582 583 A a NN 584 586 or or CC 587 594 okadaic okadaic JJ 595 599 acid acid NN 599 600 , , , 601 607 potent potent JJ 608 618 inhibitors inhibitor NNS 619 621 of of IN 622 629 protein protein NN 630 641 phosphatase phosphatase NN 642 646 type type NN 647 648 1 1 CD 649 650 ( ( ( 650 654 PP-1 pp-1 NN 654 655 ) ) ) 656 659 and and CC 660 664 type type NN 665 667 2A 2a NN 668 669 ( ( ( 669 674 PP-2A PP-2A NNP 674 675 ) ) ) 675 676 , , , 677 684 induces induce VBZ 685 688 the the DT 689 704 phosphorylation phosphorylation NN 705 707 of of IN 708 709 I i NN 710 715 kappa kappa NN 716 717 B B NNP 718 723 alpha alpha NN 724 728 even even RB 729 731 in in IN 732 735 the the DT 736 743 absence absence NN 744 746 of of IN 747 750 any any DT 751 759 cellular cellular JJ 760 768 stimulus stimulus NN 768 769 . . . 770 774 This this DT 775 781 action action NN 782 784 of of IN 785 788 the the DT 789 800 phosphatase phosphatase NN 801 811 inhibitors inhibitor NNS 811 812 , , , 813 818 which which WDT 819 821 is be VBZ 822 832 associated associate VBN 833 837 with with IN 838 841 the the DT 842 852 activation activation NN 853 855 of of IN 856 859 the the DT 860 868 RelA.p50 RelA.p50 NNP 869 877 NF-kappa NF-kappa NNP 878 879 B B NNP 880 891 heterodimer heterodimer NN 891 892 , , , 893 895 is be VBZ 896 899 not not RB 900 908 affected affect VBN 909 911 by by IN 912 918 agents agent NNS 919 923 that that WDT 924 929 block block VBP 930 933 the the DT 934 943 induction induction NN 944 946 of of IN 947 948 I i NN 949 954 kappa kappa NN 955 956 B B NNP 957 962 alpha alpha NN 963 978 phosphorylation phosphorylation NN 979 981 by by IN 982 987 tumor tumor NN 988 996 necrosis necrosis NN 997 1003 factor factor NN 1004 1009 alpha alpha NN 1010 1011 ( ( ( 1011 1020 TNF-alpha TNF-alpha NNP 1020 1021 ) ) ) 1021 1022 . . . 1023 1034 Furthermore furthermore RB 1034 1035 , , , 1036 1039 the the DT 1040 1054 phosphorylated phosphorylate VBN 1055 1056 I i NN 1057 1062 kappa kappa NN 1063 1064 B B NNP 1065 1070 alpha alpha NN 1071 1075 from from IN 1076 1085 calyculin calyculin NN 1086 1095 A-treated a-treated JJ 1096 1101 cells cell NNS 1101 1102 , , , 1103 1106 but but CC 1107 1110 not not RB 1111 1115 that that DT 1116 1120 from from IN 1121 1141 TNF-alpha-stimulated tnf-alpha-stimulated JJ 1142 1147 cells cell NNS 1147 1148 , , , 1149 1151 is be VBZ 1152 1161 sensitive sensitive JJ 1162 1164 to to TO 1165 1170 PP-2A PP-2A NNP 1171 1173 in in FW 1174 1179 vitro vitro FW 1179 1180 , , , 1181 1191 suggesting suggest VBG 1192 1195 the the DT 1196 1205 existence existence NN 1206 1208 of of IN 1209 1220 fundamental fundamental JJ 1221 1232 differences difference NNS 1233 1235 in in IN 1236 1239 the the DT 1240 1255 phosphorylation phosphorylation NN 1256 1258 of of IN 1259 1260 I i NN 1261 1266 kappa kappa NN 1267 1268 B B NNP 1269 1274 alpha alpha NN 1275 1282 induced induce VBN 1283 1285 by by IN 1286 1289 the the DT 1290 1293 two two CD 1294 1303 different different JJ 1304 1312 NF-kappa NF-kappa NNP 1313 1314 B B NNP 1315 1323 inducers inducer NNS 1323 1324 . . . 1325 1332 However however RB 1332 1333 , , , 1334 1343 induction induction NN 1344 1346 of of IN 1347 1348 I i NN 1349 1354 kappa kappa NN 1355 1356 B B NNP 1357 1362 alpha alpha NN 1363 1378 phosphorylation phosphorylation NN 1379 1381 by by IN 1382 1386 both both CC 1387 1396 TNF-alpha TNF-alpha NNP 1397 1400 and and CC 1401 1404 the the DT 1405 1416 phosphatase phosphatase NN 1417 1427 inhibitors inhibitor NNS 1428 1430 is be VBZ 1431 1441 associated associate VBN 1442 1446 with with IN 1447 1450 the the DT 1451 1461 subsequent subsequent JJ 1462 1473 degradation degradation NN 1474 1476 of of IN 1477 1478 I i NN 1479 1484 kappa kappa NN 1485 1486 B B NNP 1487 1492 alpha alpha NN 1492 1493 . . . 1494 1496 We we PRP 1497 1504 further further RB 1505 1516 demonstrate demonstrate VBP 1517 1521 that that IN 1522 1532 TNF-alpha- tnf-alpha- NN 1533 1536 and and CC 1537 1546 calyculin calyculin NN 1547 1556 A-induced a-induced JJ 1557 1558 I i NN 1559 1564 kappa kappa NN 1565 1566 B B NNP 1567 1572 alpha alpha NN 1573 1584 degradation degradation NN 1585 1593 exhibits exhibit VBZ 1594 1601 similar similar JJ 1602 1605 but but CC 1606 1609 not not RB 1610 1619 identical identical JJ 1620 1633 sensitivities sensitivity NNS 1634 1636 to to TO 1637 1638 a a DT 1639 1649 proteasome proteasome NN 1650 1659 inhibitor inhibitor NN 1659 1660 . . . 1661 1669 Together together RB 1669 1670 , , , 1671 1676 these these DT 1677 1684 results result NNS 1685 1692 suggest suggest VBP 1693 1697 that that IN 1698 1713 phosphorylation phosphorylation NN 1714 1716 of of IN 1717 1718 I i NN 1719 1724 kappa kappa NN 1725 1726 B B NNP 1727 1732 alpha alpha NN 1732 1733 , , , 1734 1742 mediated mediate VBN 1743 1750 through through IN 1751 1755 both both CC 1756 1759 the the DT 1760 1779 TNF-alpha-inducible tnf-alpha-inducible JJ 1780 1783 and and CC 1784 1787 the the DT 1788 1802 PP-2A-opposing pp-2a-opposing JJ 1803 1810 kinases kinase NNS 1810 1811 , , , 1812 1815 may may MD 1816 1821 serve serve VB 1822 1824 to to TO 1825 1831 target target NN 1832 1833 I i NN 1834 1839 kappa kappa NN 1840 1841 B B NNP 1842 1847 alpha alpha NN 1848 1851 for for IN 1852 1871 proteasome-mediated proteasome-mediated JJ 1872 1883 degradation degradation NN 1883 1884 . . .