0 15 Immortalization Immortalization NNP 16 18 of of IN 19 25 CD4(+) cd4(+) JJ 26 29 and and CC 30 36 CD8(+) cd8(+) JJ 37 38 T t NN 39 50 lymphocytes lymphocyte NNS 51 53 by by IN 54 59 human human JJ 60 66 T-cell t-cell NN 67 75 leukemia leukemia NN 76 81 virus virus NN 82 86 type type NN 87 88 1 1 CD 89 92 Tax Tax NNP 93 100 mutants mutant NNS 101 110 expressed express VBN 111 113 in in IN 114 115 a a DT 116 126 functional functional JJ 127 136 molecular molecular JJ 137 142 clone clone NN 142 143 . . . 145 148 The the DT 149 154 human human JJ 155 161 T-cell t-cell NN 162 170 leukemia leukemia NN 171 176 virus virus NN 177 181 type type NN 182 183 1 1 CD 184 185 ( ( ( 185 191 HTLV-1 HTLV-1 NNP 191 192 ) ) ) 193 208 transcriptional transcriptional JJ 209 224 trans-activator trans-activator NN 225 228 Tax tax NN 229 232 has have VBZ 233 237 been be VBN 238 250 demonstrated demonstrate VBN 251 253 to to TO 254 258 have have VB 259 271 transforming transform VBG 272 280 activity activity NN 281 283 in in IN 284 292 multiple multiple JJ 293 297 cell cell NN 298 305 culture culture NN 306 309 and and CC 310 326 transgenic-mouse transgenic-mouse NN 327 333 models model NNS 333 334 . . . 335 337 In in IN 338 346 addition addition NN 347 349 to to TO 350 360 activating activate VBG 361 374 transcription transcription NN 375 379 from from IN 380 383 the the DT 384 389 viral viral JJ 390 394 long long JJ 395 403 terminal terminal JJ 404 410 repeat repeat NN 411 412 ( ( ( 412 415 LTR LTR NNP 415 416 ) ) ) 417 424 through through IN 425 428 the the DT 429 435 cyclic cyclic JJ 436 439 AMP AMP NNP 440 448 response response NN 449 456 element element NN 457 464 binding binding NN 465 483 protein/activating protein/activate VBG 484 497 transcription transcription NN 498 504 factor factor NN 505 506 ( ( ( 506 514 CREB/ATF CREB/ATF NNP 514 515 ) ) ) 516 522 family family NN 523 525 of of IN 526 539 transcription transcription NN 540 547 factors factor NNS 547 548 , , , 549 552 Tax Tax NNP 553 562 activates activate VBZ 563 566 the the DT 567 577 expression expression NN 578 580 of of IN 581 589 multiple multiple JJ 590 598 cellular cellular JJ 599 608 promoters promoter NNS 609 616 through through IN 617 620 the the DT 621 630 NF-kappaB NF-kappaB NNP 631 638 pathway pathway NN 639 641 of of IN 642 657 transcriptional transcriptional JJ 658 668 activation activation NN 668 669 . . . 670 673 The the DT 674 677 Tax Tax NNP 678 685 mutants mutant NNS 686 689 M22 M22 NNP 690 693 and and CC 694 697 M47 M47 NNP 698 702 have have VBP 703 713 previously previously RB 714 718 been be VBN 719 731 demonstrated demonstrate VBN 732 734 to to TO 735 746 selectively selectively RB 747 755 abrogate abrogate VB 756 759 the the DT 760 767 ability ability NN 768 770 of of IN 771 774 Tax Tax NNP 775 777 to to TO 778 786 activate activate VB 787 800 transcription transcription NN 801 808 through through IN 809 812 the the DT 813 822 NF-kappaB NF-kappaB NNP 823 825 or or CC 826 834 CREB/ATF CREB/ATF NNP 835 842 pathway pathway NN 842 843 , , , 844 856 respectively respectively RB 856 857 . . . 858 863 These these DT 864 873 mutations mutation NNS 874 878 were be VBD 879 889 introduced introduce VBN 890 892 in in IN 893 896 the the DT 897 900 tax tax NN 901 905 gene gene NN 906 908 of of IN 909 912 the the DT 913 916 ACH ACH NNP 917 927 functional functional JJ 928 937 molecular molecular JJ 938 943 clone clone NN 944 946 of of IN 947 953 HTLV-1 HTLV-1 NNP 953 954 , , , 955 958 and and CC 959 964 virus virus NN 965 973 produced produce VBN 974 978 from from IN 979 982 the the DT 983 989 mutant mutant JJ 990 993 ACH ACH NNP 994 1000 clones clone NNS 1001 1004 was be VBD 1005 1013 examined examine VBN 1014 1017 for for IN 1018 1021 the the DT 1022 1029 ability ability NN 1030 1032 to to TO 1033 1042 replicate replicate VB 1043 1046 and and CC 1047 1058 immortalize immortalize VB 1059 1066 primary primary JJ 1067 1072 human human JJ 1073 1084 lymphocytes lymphocyte NNS 1084 1085 . . . 1086 1091 While while IN 1092 1097 virus virus NN 1098 1105 derived derive VBN 1106 1110 from from IN 1111 1114 the the DT 1115 1120 clone clone NN 1121 1131 containing contain VBG 1132 1135 the the DT 1136 1139 M47 M47 NNP 1140 1148 mutation mutation NN 1149 1157 retained retain VBD 1158 1161 the the DT 1162 1169 ability ability NN 1170 1172 to to TO 1173 1184 immortalize immortalize VB 1185 1186 T t NN 1187 1198 lymphocytes lymphocyte NNS 1198 1199 , , , 1200 1203 the the DT 1204 1207 M22 m22 NN 1208 1214 mutant mutant NN 1215 1219 lost lose VBD 1220 1223 the the DT 1224 1231 ability ability NN 1232 1234 to to TO 1235 1246 immortalize immortalize VB 1247 1255 infected infected JJ 1256 1261 cells cell NNS 1261 1262 . . . 1263 1268 These these DT 1269 1276 results result NNS 1277 1285 indicate indicate VBP 1286 1290 that that IN 1291 1301 activation activation NN 1302 1304 of of IN 1305 1308 the the DT 1309 1317 CREB/ATF CREB/ATF NNP 1318 1325 pathway pathway NN 1326 1328 by by IN 1329 1332 Tax Tax NNP 1333 1335 is be VBZ 1336 1347 dispensable dispensable JJ 1348 1351 for for IN 1352 1355 the the DT 1356 1371 immortalization immortalization NN 1372 1374 of of IN 1375 1376 T t NN 1377 1382 cells cell NNS 1383 1385 by by IN 1386 1392 HTLV-1 HTLV-1 NNP 1392 1393 , , , 1394 1401 whereas whereas IN 1402 1412 activation activation NN 1413 1415 of of IN 1416 1419 the the DT 1420 1429 NF-kappaB NF-kappaB NNP 1430 1437 pathway pathway NN 1438 1441 may may MD 1442 1444 be be VB 1445 1453 critical critical JJ 1453 1454 . . .