0 2 N- N- NNP 3 6 and and CC 7 17 C-terminal c-terminal JJ 18 27 sequences sequence NNS 28 35 control control VBP 36 47 degradation degradation NN 48 50 of of IN 51 57 MAD3/I MAD3/I NNP 58 63 kappa kappa NN 64 65 B B NNP 66 71 alpha alpha NN 72 74 in in IN 75 83 response response NN 84 86 to to TO 87 95 inducers inducer NNS 96 98 of of IN 99 107 NF-kappa NF-kappa NNP 108 109 B B NNP 110 118 activity activity NN 118 119 . . . 121 124 The the DT 125 136 proteolytic proteolytic JJ 137 148 degradation degradation NN 149 151 of of IN 152 155 the the DT 156 166 inhibitory inhibitory JJ 167 174 protein protein NN 175 181 MAD3/I MAD3/I NNP 182 187 kappa kappa NN 188 189 B B NNP 190 195 alpha alpha NN 196 198 in in IN 199 207 response response NN 208 210 to to TO 211 224 extracellular extracellular JJ 225 236 stimulation stimulation NN 237 239 is be VBZ 240 241 a a DT 242 254 prerequisite prerequisite JJ 255 259 step step NN 260 262 in in IN 263 266 the the DT 267 277 activation activation NN 278 280 of of IN 281 284 the the DT 285 298 transcription transcription NN 299 305 factor factor NN 306 314 NF-kappa NF-kappa NNP 315 317 B. B. NNP 318 326 Analysis Analysis NNP 327 329 of of IN 330 333 the the DT 334 344 expression expression NN 345 347 of of IN 348 353 human human JJ 354 355 I i NN 356 361 kappa kappa NN 362 363 B B NNP 364 369 alpha alpha NN 370 377 protein protein NN 378 380 in in IN 381 387 stable stable JJ 388 401 transfectants transfectant NNS 402 404 of of IN 405 410 mouse mouse NN 411 416 70Z/3 70z/3 NN 417 422 cells cell NNS 423 428 shows show VBZ 429 433 that that IN 433 434 , , , 435 437 as as IN 438 441 for for IN 442 445 the the DT 446 456 endogenous endogenous JJ 457 463 murine murine JJ 464 471 protein protein NN 471 472 , , , 473 482 exogenous exogenous JJ 483 484 I i NN 485 490 kappa kappa NN 491 492 B B NNP 493 498 alpha alpha NN 499 501 is be VBZ 502 510 degraded degrade VBN 511 513 in in IN 514 522 response response NN 523 525 to to TO 526 534 inducers inducer NNS 535 537 of of IN 538 546 NF-kappa NF-kappa NNP 547 548 B B NNP 549 557 activity activity NN 557 558 , , , 559 563 such such JJ 564 566 as as IN 567 574 phorbol phorbol NN 575 584 myristate myristate NN 585 592 acetate acetate NN 593 595 or or CC 596 614 lipopolysaccharide lipopolysaccharide NN 614 615 . . . 616 618 In in IN 619 627 addition addition NN 627 628 , , , 629 641 pretreatment pretreatment NN 642 644 of of IN 645 648 the the DT 649 654 cells cell NNS 655 659 with with IN 660 663 the the DT 664 674 proteasome proteasome NN 675 684 inhibitor inhibitor NN 685 709 N-Ac-Leu-Leu-norleucinal N-Ac-Leu-Leu-norleucinal NNP 710 718 inhibits inhibit VBZ 719 723 this this DT 724 738 ligand-induced ligand-induced JJ 739 750 degradation degradation NN 751 754 and and CC 754 755 , , , 756 758 in in IN 759 768 agreement agreement NN 769 773 with with IN 774 782 previous previous JJ 783 790 studies study NNS 790 791 , , , 792 802 stabilizes stabilize VBZ 803 804 a a DT 805 824 hyperphosphorylated hyperphosphorylate VBN 825 829 form form NN 830 832 of of IN 833 836 the the DT 837 842 human human JJ 843 844 I i NN 845 850 kappa kappa NN 851 852 B B NNP 853 858 alpha alpha NN 859 866 protein protein NN 866 867 . . . 868 870 By by IN 871 881 expressing express VBG 882 888 mutant mutant JJ 889 894 forms form NNS 895 897 of of IN 898 901 the the DT 902 907 human human JJ 908 915 protein protein NN 916 918 in in IN 919 923 this this DT 924 928 cell cell NN 929 933 line line NN 933 934 , , , 935 937 we we PRP 938 942 have have VBP 943 947 been be VBN 948 952 able able JJ 953 955 to to TO 956 965 delineate delineate VB 966 969 the the DT 970 979 sequences sequence NNS 980 991 responsible responsible JJ 992 995 for for IN 996 1000 both both CC 1001 1004 the the DT 1005 1019 ligand-induced ligand-induced JJ 1020 1035 phosphorylation phosphorylation NN 1036 1039 and and CC 1040 1043 the the DT 1044 1055 degradation degradation NN 1056 1058 of of IN 1059 1060 I i NN 1061 1066 kappa kappa NN 1067 1068 B B NNP 1069 1074 alpha alpha NN 1074 1075 . . . 1076 1079 Our our PRP$ 1080 1087 results result NNS 1088 1092 show show VBP 1093 1097 that that IN 1098 1106 deletion deletion NN 1107 1109 of of IN 1110 1113 the the DT 1114 1115 C C NNP 1116 1124 terminus terminus NN 1125 1127 of of IN 1128 1131 the the DT 1132 1133 I i NN 1134 1139 kappa kappa NN 1140 1141 B B NNP 1142 1147 alpha alpha NN 1148 1156 molecule molecule NN 1157 1159 up up IN 1160 1162 to to TO 1163 1168 amino amino JJ 1169 1173 acid acid NN 1174 1177 279 279 CD 1178 1187 abolishes abolish VBZ 1188 1200 constitutive constitutive JJ 1201 1204 but but CC 1205 1208 not not RB 1209 1225 ligand-inducible ligand-inducible JJ 1226 1241 phosphorylation phosphorylation NN 1242 1245 and and CC 1246 1254 inhibits inhibit VBZ 1255 1271 ligand-inducible ligand-inducible JJ 1272 1283 degradation degradation NN 1283 1284 . . . 1285 1292 Further further JJ 1293 1301 analysis analysis NN 1302 1309 reveals reveal VBZ 1310 1314 that that IN 1315 1318 the the DT 1319 1328 inducible inducible JJ 1329 1344 phosphorylation phosphorylation NN 1345 1347 of of IN 1348 1349 I i NN 1350 1355 kappa kappa NN 1356 1357 B B NNP 1358 1363 alpha alpha NN 1364 1368 maps map VBZ 1369 1371 to to TO 1372 1375 two two CD 1376 1383 serines serine NNS 1384 1386 in in IN 1387 1390 the the DT 1391 1392 N N NNP 1393 1401 terminus terminus NN 1402 1404 of of IN 1405 1408 the the DT 1409 1416 protein protein NN 1417 1418 ( ( ( 1418 1426 residues residue NNS 1427 1429 32 32 CD 1430 1433 and and CC 1434 1436 36 36 CD 1436 1437 ) ) ) 1438 1441 and and CC 1442 1446 that that IN 1447 1450 the the DT 1451 1459 mutation mutation NN 1460 1462 of of IN 1463 1469 either either DT 1470 1477 residue residue NN 1478 1480 is be VBZ 1481 1491 sufficient sufficient JJ 1492 1494 to to TO 1495 1502 abolish abolish VB 1503 1517 ligand-induced ligand-induced JJ 1518 1529 degradation degradation NN 1529 1530 , , , 1531 1538 whereas whereas IN 1539 1543 both both DT 1544 1552 residues residue NNS 1553 1557 must must MD 1558 1560 be be VB 1561 1568 mutated mutate VBN 1569 1571 to to TO 1572 1579 abolish abolish VB 1580 1589 inducible inducible JJ 1590 1605 phosphorylation phosphorylation NN 1606 1608 of of IN 1609 1612 the the DT 1613 1620 protein protein NN 1620 1621 . . . 1622 1623 ( ( ( 1623 1631 ABSTRACT abstract NN 1632 1641 TRUNCATED truncated VBN 1642 1644 AT at IN 1645 1648 250 250 CD 1649 1654 WORDS words NNS 1654 1655 ) ) )