0 16 Characterization characterization NN 17 19 of of IN 20 21 a a DT 22 28 mutant mutant JJ 29 33 cell cell NN 34 38 line line NN 39 43 that that WDT 44 48 does do VBZ 49 52 not not RB 53 61 activate activate VB 62 71 NF-kappaB nf-kappab NN 72 74 in in IN 75 83 response response NN 84 86 to to TO 87 95 multiple multiple JJ 96 103 stimuli stimulus NNS 103 104 . . . 106 114 Numerous numerous JJ 115 120 genes gene NNS 121 129 required require VBN 130 136 during during IN 137 140 the the DT 141 147 immune immune JJ 148 150 or or CC 151 163 inflammation inflammation NN 164 172 response response NN 173 175 as as RB 176 180 well well RB 181 183 as as IN 184 187 the the DT 188 196 adhesion adhesion NN 197 204 process process NN 205 208 are be VBP 209 218 regulated regulate VBN 219 221 by by IN 222 229 nuclear nuclear JJ 230 236 factor factor NN 237 243 kappaB kappaB NNP 244 245 ( ( ( 245 254 NF-kappaB NF-kappaB NNP 254 255 ) ) ) 255 256 . . . 257 267 Associated associate VBN 268 272 with with IN 273 276 its its PRP$ 277 286 inhibitor inhibitor NN 286 287 , , , 288 289 I i NN 290 296 kappaB kappaB NNP 296 297 , , , 298 307 NF-kappaB NF-kappaB NNP 308 315 resides reside VBZ 316 318 as as IN 319 321 an an DT 322 330 inactive inactive JJ 331 335 form form NN 336 338 in in IN 339 342 the the DT 343 352 cytoplasm cytoplasm NN 352 353 . . . 354 358 Upon upon IN 359 370 stimulation stimulation NN 371 373 by by IN 374 381 various various JJ 382 388 agents agent NNS 388 389 , , , 390 391 I i NN 392 398 kappaB kappaB NNP 399 401 is be VBZ 402 413 proteolyzed proteolyze VBN 414 417 and and CC 418 427 NF-kappaB NF-kappaB NNP 428 440 translocates translocate VBZ 441 443 to to TO 444 447 the the DT 448 455 nucleus nucleus NN 455 456 , , , 457 462 where where WRB 463 465 it it PRP 466 475 activates activate VBZ 476 479 its its PRP$ 480 486 target target NN 487 492 genes gene NNS 492 493 . . . 494 497 The the DT 498 510 transduction transduction NN 511 519 pathways pathway NNS 520 524 that that WDT 525 529 lead lead VBP 530 532 to to TO 533 534 I i NN 535 541 kappaB kappab NN 542 554 inactivation inactivation NN 555 561 remain remain VBP 562 568 poorly poorly RB 569 579 understood understand VBN 579 580 . . . 581 583 In in IN 584 588 this this DT 589 594 study study NN 594 595 , , , 596 598 we we PRP 599 603 have have VBP 604 617 characterized characterize VBN 618 619 a a DT 620 628 cellular cellular JJ 629 635 mutant mutant NN 635 636 , , , 637 640 the the DT 641 654 70/Z3-derived 70/z3-derived JJ 655 660 1.3E2 1.3e2 NN 661 667 murine murine JJ 668 673 pre-B pre-b JJ 674 678 cell cell NN 679 683 line line NN 683 684 , , , 685 689 that that WDT 690 694 does do VBZ 695 698 not not RB 699 707 activate activate VB 708 717 NF-kappaB nf-kappab NN 718 720 in in IN 721 729 response response NN 730 732 to to TO 733 740 several several JJ 741 748 stimuli stimulus NNS 748 749 . . . 750 752 We we PRP 753 764 demonstrate demonstrate VBP 765 769 that that IN 770 774 upon upon IN 775 786 stimulation stimulation NN 787 789 by by IN 790 808 lipopolysaccharide lipopolysaccharide NN 808 809 , , , 810 815 Taxol Taxol NNP 815 816 , , , 817 824 phorbol phorbol NN 825 834 myristate myristate NN 835 842 acetate acetate NN 842 843 , , , 844 857 interleukin-1 interleukin-1 NN 857 858 , , , 859 861 or or CC 862 877 double-stranded double-stranded JJ 878 881 RNA RNA NNP 881 882 , , , 883 884 I i NN 885 891 kappaB kappab NN 892 897 alpha alpha NN 898 900 is be VBZ 901 904 not not RB 905 913 degraded degrade VBN 913 914 , , , 915 917 as as IN 918 919 a a DT 920 926 result result NN 927 929 of of IN 930 932 an an DT 933 940 absence absence NN 941 943 of of IN 944 951 induced induce VBN 952 967 phosphorylation phosphorylation NN 968 970 on on IN 971 978 serines serine NNS 979 981 32 32 CD 982 985 and and CC 986 988 36 36 CD 988 989 . . . 990 997 Neither neither CC 998 999 a a DT 1000 1008 mutation mutation NN 1009 1011 in in IN 1012 1013 I i NN 1014 1020 kappaB kappab NN 1021 1026 alpha alpha NN 1027 1030 nor nor CC 1031 1032 a a DT 1033 1041 mutation mutation NN 1042 1044 in in IN 1045 1048 p50 p50 NN 1049 1051 or or CC 1052 1056 relA relA NNP 1056 1057 , , , 1058 1061 the the DT 1062 1065 two two CD 1066 1071 major major JJ 1072 1080 subunits subunit NNS 1081 1083 of of IN 1084 1093 NF-kappaB NF-kappaB NNP 1094 1096 in in IN 1097 1101 this this DT 1102 1106 cell cell NN 1107 1111 line line NN 1111 1112 , , , 1113 1121 accounts account VBZ 1122 1125 for for IN 1126 1130 this this DT 1131 1146 phosphorylation phosphorylation NN 1147 1153 defect defect NN 1153 1154 . . . 1155 1157 As as RB 1158 1162 well well RB 1163 1165 as as IN 1166 1177 culminating culminate VBG 1178 1180 in in IN 1181 1184 the the DT 1185 1194 inducible inducible JJ 1195 1210 phosphorylation phosphorylation NN 1211 1213 of of IN 1214 1215 I i NN 1216 1222 kappaB kappab NN 1223 1228 alpha alpha NN 1229 1231 on on IN 1232 1239 serines serine NNS 1240 1242 32 32 CD 1243 1246 and and CC 1247 1249 36 36 CD 1249 1250 , , , 1251 1254 all all PDT 1255 1258 the the DT 1259 1266 stimuli stimulus NNS 1267 1271 that that WDT 1272 1275 are be VBP 1276 1284 inactive inactive JJ 1285 1287 on on IN 1288 1293 1.3E2 1.3e2 NN 1294 1299 cells cell NNS 1300 1307 exhibit exhibit VBP 1308 1309 a a DT 1310 1321 sensitivity sensitivity NN 1322 1324 to to TO 1325 1328 the the DT 1329 1340 antioxidant antioxidant JJ 1341 1352 pyrrolidine pyrrolidine NN 1353 1368 dithiocarbamate dithiocarbamate NN 1369 1370 ( ( ( 1370 1374 PDTC PDTC NNP 1374 1375 ) ) ) 1375 1376 . . . 1377 1379 In in IN 1380 1388 contrast contrast NN 1388 1389 , , , 1390 1397 stimuli stimulus NNS 1398 1402 such such JJ 1403 1405 as as IN 1406 1418 hyperosmotic hyperosmotic JJ 1419 1424 shock shock NN 1425 1427 or or CC 1428 1439 phosphatase phosphatase NN 1440 1450 inhibitors inhibitor NNS 1450 1451 , , , 1452 1457 which which WDT 1458 1461 use use VBP 1462 1478 PDTC-insensitive pdtc-insensitive JJ 1479 1487 pathways pathway NNS 1487 1488 , , , 1489 1495 induce induce VBP 1496 1497 I i NN 1498 1504 kappaB kappab NN 1505 1510 alpha alpha NN 1511 1522 degradation degradation NN 1523 1525 in in IN 1526 1531 1.3E2 1.3e2 NN 1531 1532 . . . 1533 1541 Analysis Analysis NNP 1542 1544 of of IN 1545 1548 the the DT 1549 1554 redox redox NN 1555 1561 status status NN 1562 1564 of of IN 1565 1570 1.3E2 1.3e2 NN 1571 1575 does do VBZ 1576 1579 not not RB 1580 1586 reveal reveal VB 1587 1590 any any DT 1591 1601 difference difference NN 1602 1606 from from IN 1607 1616 wild-type wild-type JJ 1617 1622 70Z/3 70z/3 NN 1622 1623 . . . 1624 1626 We we PRP 1627 1631 also also RB 1632 1638 report report VBP 1639 1643 that that IN 1644 1647 the the DT 1648 1653 human human JJ 1654 1660 T-cell t-cell NN 1661 1669 leukemia leukemia NN 1670 1675 virus virus NN 1676 1680 type type NN 1681 1682 1 1 CD 1683 1684 ( ( ( 1684 1699 HTLV-1)-derived htlv-1)-derived JJ 1700 1703 Tax Tax NNP 1704 1719 trans-activator trans-activator NN 1720 1727 induces induce VBZ 1728 1737 NF-kappaB NF-kappaB NNP 1738 1746 activity activity NN 1747 1749 in in IN 1750 1755 1.3E2 1.3e2 NN 1755 1756 , , , 1757 1767 suggesting suggest VBG 1768 1772 that that IN 1773 1777 this this DT 1778 1783 viral viral JJ 1784 1791 protein protein NN 1792 1796 does do VBZ 1797 1800 not not RB 1801 1808 operate operate VB 1809 1812 via via IN 1813 1816 the the DT 1817 1826 defective defective JJ 1827 1834 pathway pathway NN 1834 1835 . . . 1836 1843 Finally finally RB 1843 1844 , , , 1845 1847 we we PRP 1848 1852 show show VBP 1853 1857 that that IN 1858 1861 two two CD 1862 1867 other other JJ 1868 1869 I i NN 1870 1876 kappaB kappab NN 1877 1886 molecules molecule NNS 1886 1887 , , , 1888 1889 I i NN 1890 1896 kappaB kappab NN 1897 1901 beta beta NN 1902 1905 and and CC 1906 1909 the the DT 1910 1918 recently recently RB 1919 1929 identified identify VBN 1930 1931 I i NN 1932 1938 kappaB kappab NN 1939 1946 epsilon epsilon NN 1946 1947 , , , 1948 1951 are be VBP 1952 1955 not not RB 1956 1964 degraded degrade VBN 1965 1967 in in IN 1968 1971 the the DT 1972 1977 1.3E2 1.3e2 NN 1978 1982 cell cell NN 1983 1987 line line NN 1988 1997 following follow VBG 1998 2009 stimulation stimulation NN 2009 2010 . . . 2011 2014 Our our PRP$ 2015 2022 results result NNS 2023 2034 demonstrate demonstrate VBP 2035 2039 that that IN 2040 2045 1.3E2 1.3e2 NN 2046 2048 is be VBZ 2049 2050 a a DT 2051 2059 cellular cellular JJ 2060 2072 transduction transduction NN 2073 2079 mutant mutant NN 2080 2090 exhibiting exhibit VBG 2091 2092 a a DT 2093 2099 defect defect NN 2100 2102 in in IN 2103 2104 a a DT 2105 2109 step step NN 2110 2114 that that WDT 2115 2117 is be VBZ 2118 2126 required require VBN 2127 2129 by by IN 2130 2137 several several JJ 2138 2147 different different JJ 2148 2155 stimuli stimulus NNS 2156 2158 to to TO 2159 2167 activate activate VB 2168 2177 NF-kappaB NF-kappaB NNP 2177 2178 . . . 2179 2181 In in IN 2182 2190 addition addition NN 2190 2191 , , , 2192 2196 this this DT 2197 2205 analysis analysis NN 2206 2214 suggests suggest VBZ 2215 2216 a a DT 2217 2223 common common JJ 2224 2228 step step NN 2229 2231 in in IN 2232 2235 the the DT 2236 2245 signaling signaling NN 2246 2254 pathways pathway NNS 2255 2259 that that WDT 2260 2267 trigger trigger VBP 2268 2269 I i NN 2270 2276 kappaB kappab NN 2277 2282 alpha alpha NN 2282 2283 , , , 2284 2285 I i NN 2286 2292 kappaB kappab NN 2293 2297 beta beta NN 2297 2298 , , , 2299 2302 and and CC 2303 2304 I i NN 2305 2311 kappaB kappab NN 2312 2319 epsilon epsilon NN 2320 2331 degradation degradation NN 2331 2332 . . .