0 5 Human human JJ 6 12 T-cell T-cell NNP 13 21 leukemia leukemia NN 22 27 virus virus NN 28 32 type type NN 33 34 1 1 CD 35 38 Tax tax NN 39 48 induction induction NN 49 51 of of IN 52 61 NF-kappaB NF-kappaB NNP 62 70 involves involve VBZ 71 81 activation activation NN 82 84 of of IN 85 88 the the DT 89 96 IkappaB IkappaB NNP 97 103 kinase kinase NNP 104 109 alpha alpha NN 110 111 ( ( ( 111 119 IKKalpha IKKalpha NNP 119 120 ) ) ) 121 124 and and CC 125 132 IKKbeta IKKbeta NNP 133 141 cellular cellular JJ 142 149 kinases kinase NNS 149 150 . . . 152 155 Tax Tax NNP 156 167 corresponds correspond VBZ 168 170 to to TO 171 172 a a DT 173 179 40-kDa 40-kda JJ 180 192 transforming transform VBG 193 200 protein protein NN 201 205 from from IN 206 209 the the DT 210 220 pathogenic pathogenic JJ 221 231 retrovirus retrovirus NN 232 237 human human JJ 238 244 T-cell t-cell NN 245 253 leukemia leukemia NN 254 259 virus virus NN 260 264 type type NN 265 266 1 1 CD 267 268 ( ( ( 268 274 HTLV-1 HTLV-1 NNP 274 275 ) ) ) 276 280 that that WDT 281 290 activates activate VBZ 291 298 nuclear nuclear JJ 299 309 expression expression NN 310 312 of of IN 313 316 the the DT 317 330 NF-kappaB/Rel NF-kappaB/Rel NNP 331 337 family family NN 338 340 of of IN 341 354 transcription transcription NN 355 362 factors factor NNS 363 365 by by IN 366 368 an an DT 369 376 unknown unknown JJ 377 386 mechanism mechanism NN 386 387 . . . 388 391 Tax Tax NNP 392 402 expression expression NN 403 411 promotes promote VBZ 412 422 N-terminal n-terminal JJ 423 438 phosphorylation phosphorylation NN 439 442 and and CC 443 454 degradation degradation NN 455 457 of of IN 458 465 IkappaB IkappaB NNP 466 471 alpha alpha NN 471 472 , , , 473 474 a a DT 475 484 principal principal JJ 485 496 cytoplasmic cytoplasmic JJ 497 506 inhibitor inhibitor NN 507 509 of of IN 510 519 NF-kappaB NF-kappaB NNP 519 520 . . . 521 524 Our our PRP$ 525 532 studies study NNS 533 536 now now RB 537 548 demonstrate demonstrate VBP 549 553 that that IN 554 560 HTLV-1 HTLV-1 NNP 561 564 Tax Tax NNP 565 574 activates activate VBZ 575 578 the the DT 579 587 recently recently RB 588 598 identified identify VBN 599 607 cellular cellular JJ 608 615 kinases kinase NNS 616 623 IkappaB IkappaB NNP 624 630 kinase kinase NNP 631 636 alpha alpha NN 637 638 ( ( ( 638 646 IKKalpha IKKalpha NNP 646 647 ) ) ) 648 651 and and CC 652 659 IKKbeta IKKbeta NNP 659 660 , , , 661 666 which which WDT 667 675 normally normally RB 676 689 phosphorylate phosphorylate VBP 690 697 IkappaB IkappaB NNP 698 703 alpha alpha NN 704 706 on on IN 707 711 both both DT 712 714 of of IN 715 718 its its PRP$ 719 729 N-terminal n-terminal JJ 730 740 regulatory regulatory JJ 741 748 serines serine NNS 749 751 in in IN 752 760 response response NN 761 763 to to TO 764 769 tumor tumor NN 770 778 necrosis necrosis NN 779 785 factor factor NN 786 791 alpha alpha NN 792 793 ( ( ( 793 802 TNF-alpha TNF-alpha NNP 802 803 ) ) ) 804 807 and and CC 808 821 interleukin-1 interleukin-1 NN 822 823 ( ( ( 823 827 IL-1 il-1 NN 827 828 ) ) ) 829 840 stimulation stimulation NN 840 841 . . . 842 844 In in IN 845 853 contrast contrast NN 853 854 , , , 855 856 a a DT 857 863 mutant mutant NN 864 866 of of IN 867 870 Tax Tax NNP 871 877 termed term VBN 878 881 M22 m22 NN 881 882 , , , 883 888 which which WDT 889 893 does do VBZ 894 897 not not RB 898 904 induce induce VB 905 914 NF-kappaB NF-kappaB NNP 914 915 , , , 916 921 fails fail VBZ 922 924 to to TO 925 933 activate activate VB 934 940 either either CC 941 949 IKKalpha IKKalpha NNP 950 952 or or CC 953 960 IKKbeta IKKbeta NNP 960 961 . . . 962 973 Furthermore furthermore RB 973 974 , , , 975 985 endogenous endogenous JJ 986 989 IKK IKK NNP 990 999 enzymatic enzymatic JJ 1000 1008 activity activity NN 1009 1012 was be VBD 1013 1026 significantly significantly RB 1027 1035 elevated elevated JJ 1036 1038 in in IN 1039 1054 HTLV-1-infected htlv-1-infected JJ 1055 1058 and and CC 1059 1073 Tax-expressing tax-expressing JJ 1074 1080 T-cell t-cell NN 1081 1086 lines line NNS 1086 1087 . . . 1088 1100 Transfection transfection NN 1101 1103 of of IN 1104 1120 kinase-deficient kinase-deficient JJ 1121 1128 mutants mutant NNS 1129 1131 of of IN 1132 1140 IKKalpha IKKalpha NNP 1141 1144 and and CC 1145 1152 IKKbeta IKKbeta NNP 1153 1157 into into IN 1158 1164 either either CC 1165 1170 human human JJ 1171 1177 Jurkat Jurkat NNP 1178 1179 T t NN 1180 1182 or or CC 1183 1186 293 293 CD 1187 1192 cells cell NNS 1193 1197 also also RB 1198 1206 inhibits inhibit VBZ 1207 1226 NF-kappaB-dependent nf-kappab-dependent JJ 1227 1235 reporter reporter NN 1236 1240 gene gene NN 1241 1251 expression expression NN 1252 1259 induced induce VBN 1260 1262 by by IN 1263 1266 Tax Tax NNP 1266 1267 . . . 1268 1277 Similarly similarly RB 1277 1278 , , , 1279 1280 a a DT 1281 1297 kinase-deficient kinase-deficient JJ 1298 1304 mutant mutant NN 1305 1307 of of IN 1308 1311 NIK NIK NNP 1312 1313 ( ( ( 1313 1331 NF-kappaB-inducing NF-kappaB-inducing NNP 1332 1338 kinase kinase NNP 1338 1339 ) ) ) 1339 1340 , , , 1341 1346 which which WDT 1347 1357 represents represent VBZ 1358 1360 an an DT 1361 1369 upstream upstream JJ 1370 1376 kinase kinase NN 1377 1379 in in IN 1380 1383 the the DT 1384 1393 TNF-alpha TNF-alpha NNP 1394 1397 and and CC 1398 1402 IL-1 il-1 NN 1403 1412 signaling signaling NN 1413 1421 pathways pathway NNS 1422 1429 leading lead VBG 1430 1432 to to TO 1433 1441 IKKalpha IKKalpha NNP 1442 1445 and and CC 1446 1453 IKKbeta IKKbeta NNP 1454 1464 activation activation NN 1464 1465 , , , 1466 1472 blocks block VBZ 1473 1476 Tax Tax NNP 1477 1486 induction induction NN 1487 1489 of of IN 1490 1499 NF-kappaB NF-kappaB NNP 1499 1500 . . . 1501 1508 However however RB 1508 1509 , , , 1510 1516 plasma plasma NN 1517 1534 membrane-proximal membrane-proximal JJ 1535 1543 elements element NNS 1544 1546 in in IN 1547 1552 these these DT 1553 1568 proinflammatory proinflammatory JJ 1569 1577 cytokine cytokine NN 1578 1586 pathways pathway NNS 1587 1590 are be VBP 1591 1601 apparently apparently RB 1602 1605 not not RB 1606 1614 involved involve VBN 1615 1620 since since IN 1621 1629 dominant dominant JJ 1630 1638 negative negative JJ 1639 1646 mutants mutant NNS 1647 1649 of of IN 1650 1653 the the DT 1654 1659 TRAF2 traf2 NN 1660 1663 and and CC 1664 1669 TRAF6 traf6 NN 1670 1678 adaptors adaptor NNS 1678 1679 , , , 1680 1685 which which WDT 1686 1697 effectively effectively RB 1698 1703 block block VBP 1704 1713 signaling signal VBG 1714 1721 through through IN 1722 1725 the the DT 1726 1737 cytoplasmic cytoplasmic JJ 1738 1743 tails tail NNS 1744 1746 of of IN 1747 1750 the the DT 1751 1760 TNF-alpha TNF-alpha NNP 1761 1764 and and CC 1765 1769 IL-1 il-1 NN 1770 1779 receptors receptor NNS 1779 1780 , , , 1781 1793 respectively respectively RB 1793 1794 , , , 1795 1797 do do VBP 1798 1801 not not RB 1802 1809 inhibit inhibit VB 1810 1813 Tax Tax NNP 1814 1823 induction induction NN 1824 1826 of of IN 1827 1836 NF-kappaB NF-kappaB NNP 1836 1837 . . . 1838 1846 Together together RB 1846 1847 , , , 1848 1853 these these DT 1854 1861 studies study NNS 1862 1873 demonstrate demonstrate VBP 1874 1878 that that IN 1879 1885 HTLV-1 HTLV-1 NNP 1886 1889 Tax Tax NNP 1890 1898 exploits exploit VBZ 1899 1900 a a DT 1901 1907 distal distal JJ 1908 1912 part part NN 1913 1915 of of IN 1916 1919 the the DT 1920 1935 proinflammatory proinflammatory JJ 1936 1944 cytokine cytokine NN 1945 1954 signaling signaling NN 1955 1962 cascade cascade NN 1963 1970 leading lead VBG 1971 1973 to to TO 1974 1983 induction induction NN 1984 1986 of of IN 1987 1996 NF-kappaB NF-kappaB NNP 1996 1997 . . . 1998 2001 The the DT 2002 2014 pathological pathological JJ 2015 2025 alteration alteration NN 2026 2028 of of IN 2029 2033 this this DT 2034 2042 cytokine cytokine NN 2043 2050 pathway pathway NN 2051 2058 leading lead VBG 2059 2061 to to TO 2062 2071 NF-kappaB NF-kappaB NNP 2072 2082 activation activation NN 2083 2085 by by IN 2086 2089 Tax Tax NNP 2090 2093 may may MD 2094 2098 play play VB 2099 2100 a a DT 2101 2108 central central JJ 2109 2113 role role NN 2114 2116 in in IN 2117 2132 HTLV-1-mediated htlv-1-mediated JJ 2133 2147 transformation transformation NN 2148 2150 of of IN 2151 2156 human human JJ 2157 2158 T t NN 2159 2164 cells cell NNS 2164 2165 , , , 2166 2176 clinically clinically RB 2177 2187 manifested manifest VBN 2188 2190 as as IN 2191 2194 the the DT 2195 2200 adult adult JJ 2201 2207 T-cell t-cell NN 2208 2216 leukemia leukemia NN 2216 2217 . . .