0 3 The the DT 4 16 Epstein-Barr epstein-barr JJ 17 22 virus virus NN 23 30 latency latency NN 31 38 BamHI-Q BamHI-Q NNP 39 47 promoter promoter NN 48 50 is be VBZ 51 61 positively positively RB 62 71 regulated regulate VBN 72 74 by by IN 75 80 STATs STAT NNP 81 84 and and CC 85 88 Zta Zta NNP 89 101 interference interference NN 102 106 with with IN 107 115 JAK/STAT jak/stat JJ|NN 116 126 activation activation NN 127 132 leads lead VBZ 133 135 to to TO 136 140 loss loss NN 141 143 of of IN 144 151 BamHI-Q BamHI-Q NNP 152 160 promoter promoter NN 161 169 activity activity NN 169 170 . . . 172 174 In in IN 175 187 Epstein-Barr epstein-barr JJ 188 193 virus virus NN 194 195 ( ( ( 195 210 EBV)-associated ebv)-associated JJ 211 217 tumors tumor NNS 218 220 in in IN 221 241 nonimmunocompromised nonimmunocompromised JJ 242 250 patients patient NNS 250 251 , , , 252 255 EBV EBV NNP 256 260 gene gene NN 261 271 expression expression NN 272 274 is be VBZ 275 281 highly highly RB 282 292 restricted restricted JJ 292 293 . . . 294 305 EBV-encoded ebv-encoded JJ 306 313 nuclear nuclear JJ 314 321 antigen antigen NN 322 323 ( ( ( 323 330 EBNA)-1 EBNA)-1 NNP 331 333 is be VBZ 334 343 expressed express VBN 343 344 , , , 345 352 whereas whereas IN 353 356 the the DT 357 368 immunogenic immunogenic JJ 369 372 and and CC 373 386 proliferative proliferative JJ 387 392 EBNAs ebna NNS 393 396 are be VBP 397 400 not not RB 400 401 . . . 402 406 This this DT 407 414 pattern pattern NN 415 417 of of IN 418 422 EBNA EBNA NNP 423 433 expression expression NN 434 436 is be VBZ 437 446 generated generate VBN 447 449 by by IN 450 455 usage usage NN 456 458 of of IN 459 462 the the DT 463 470 BamHI-Q BamHI-Q NNP 471 479 promoter promoter NN 480 481 ( ( ( 481 483 Qp Qp NNP 483 484 ) ) ) 484 485 . . . 486 488 We we PRP 489 493 have have VBP 494 504 determined determine VBN 505 509 that that IN 510 513 the the DT 514 522 JAK/STAT JAK/STAT NNP 523 530 pathway pathway NN 531 541 positively positively RB 542 551 regulates regulate VBZ 552 554 Qp Qp NNP 555 563 activity activity NN 563 564 . . . 565 567 In in IN 568 590 transient-transfection transient-transfection NN 591 597 assays assay NNS 597 598 , , , 599 600 a a DT 601 607 Qp-CAT Qp-CAT NNP 608 616 reporter reporter NN 617 620 was be VBD 621 630 activated activate VBN 631 633 by by IN 634 647 cotransfected cotransfecte VBN 648 653 JAK-1 jak-1 NN 654 657 and and CC 658 660 by by IN 661 670 treatment treatment NN 671 673 of of IN 674 679 cells cell NNS 680 684 with with IN 685 688 the the DT 689 697 cytokine cytokine NN 698 702 IL-6 il-6 NN 702 703 . . . 704 707 The the DT 708 715 ability ability NN 716 718 of of IN 719 721 Qp Qp NNP 722 724 to to TO 725 729 bind bind VB 730 736 signal signal NN 737 747 transducer transducer NN 748 751 and and CC 752 761 activator activator NN 762 764 of of IN 765 778 transcription transcription NN 779 780 ( ( ( 780 784 STAT STAT NNP 784 785 ) ) ) 786 794 proteins protein NNS 795 798 was be VBD 799 807 directly directly RB 808 820 demonstrated demonstrate VBN 821 823 by by IN 824 839 electrophoretic electrophoretic JJ 840 854 mobility-shift mobility-shift JJ|NN 855 860 assay assay NN 860 861 , , , 862 865 and and CC 866 874 mutation mutation NN 875 877 of of IN 878 887 potential potential JJ 888 900 STAT-binding stat-binding JJ 901 906 sites site NNS 907 914 reduced reduce VBD 915 917 Qp Qp NNP 918 932 responsiveness responsiveness NN 933 935 to to TO 936 941 Janus Janus NNP 942 948 kinase kinase NNP 949 950 ( ( ( 950 956 JAK)-1 JAK)-1 NNP 956 957 . . . 958 968 Consistent consistent JJ 969 973 with with IN 974 975 a a DT 976 980 role role NN 981 984 for for IN 985 990 STATs stat NNS 991 993 in in IN 994 996 Qp Qp NNP 997 1005 function function NN 1005 1006 , , , 1007 1009 Qp Qp NNP 1010 1015 using use VBG 1016 1023 Burkitt Burkitt NNP 1023 1025 ’s 's POS 1026 1034 lymphoma lymphoma NN 1035 1039 Rael Rael NNP 1040 1045 cells cell NNS 1046 1049 and and CC 1050 1058 cultured culture VBN 1059 1073 nasopharyngeal nasopharyngeal JJ 1074 1083 carcinoma carcinoma NN 1084 1085 ( ( ( 1085 1088 NPC NPC NNP 1088 1089 ) ) ) 1090 1095 cells cell NNS 1096 1105 contained contain VBD 1106 1113 nuclear nuclear JJ 1114 1118 STAT stat NN 1119 1126 protein protein NN 1126 1127 . . . 1128 1130 We we PRP 1131 1143 investigated investigate VBD 1144 1151 whether whether IN 1152 1155 the the DT 1156 1165 inability inability NN 1166 1168 to to TO 1169 1177 maintain maintain VB 1178 1190 EBV-positive ebv-positive JJ 1191 1194 NPC NPC NNP 1195 1199 cell cell NN 1200 1205 lines line NNS 1206 1208 in in IN 1209 1216 culture culture NN 1217 1220 was be VBD 1221 1228 related related JJ 1229 1231 to to TO 1232 1234 Qp qp NN 1235 1243 activity activity NN 1243 1244 . . . 1245 1254 Passaging passaging NN 1255 1257 of of IN 1258 1261 the the DT 1262 1265 NPC NPC NNP 1266 1270 cell cell NN 1271 1275 line line NN 1276 1281 HK666 hk666 NN 1282 1285 led lead VBD 1286 1288 to to TO 1289 1299 activation activation NN 1300 1302 of of IN 1303 1313 expression expression NN 1314 1316 of of IN 1317 1322 BZLF1 BZLF1 NNP 1322 1323 , , , 1324 1329 which which WDT 1330 1337 encodes encode VBZ 1338 1341 Zta Zta NNP 1342 1345 and and CC 1346 1350 loss loss NN 1351 1353 of of IN 1354 1356 Qp Qp NNP 1357 1365 function function NN 1365 1366 . . . 1367 1376 Transient transient JJ 1377 1387 expression expression NN 1388 1394 assays assay NNS 1395 1401 linked link VBD 1402 1405 Zta Zta NNP 1406 1416 expression expression NN 1417 1419 to to TO 1420 1423 the the DT 1424 1439 down-regulation down-regulation NN 1440 1442 of of IN 1443 1445 Qp Qp NNP 1445 1446 . . . 1447 1461 Cotransfection Cotransfection NNP 1462 1464 of of IN 1465 1468 Zta Zta NNP 1469 1476 reduced reduce VBD 1477 1479 Qp Qp NNP 1480 1488 activity activity NN 1489 1491 in in IN 1492 1500 reporter reporter NN 1501 1507 assays assay NNS 1507 1508 . . . 1509 1513 This this DT 1514 1522 negative negative JJ 1523 1533 regulation regulation NN 1534 1542 required require VBD 1543 1546 Zta Zta NNP 1547 1558 DNA-binding dna-binding JJ 1559 1567 activity activity NN 1567 1568 . . . 1569 1571 We we PRP 1572 1579 provide provide VBP 1580 1588 evidence evidence NN 1589 1593 that that IN 1594 1597 Zta Zta NNP 1598 1611 up-regulation up-regulation NN 1612 1614 of of IN 1615 1618 p53 p53 NN 1619 1624 leads lead VBZ 1625 1627 to to TO 1628 1640 p53-mediated p53-mediated JJ 1641 1653 interference interference NN 1654 1658 with with IN 1659 1667 JAK/STAT JAK/STAT NNP 1668 1678 activation activation NN 1679 1681 of of IN 1682 1684 Qp Qp NNP 1684 1685 . . . 1686 1689 The the DT 1690 1694 data datum NNS 1695 1700 imply imply VBP 1701 1705 that that IN 1706 1714 JAK/STAT jak/stat JJ|NN 1715 1724 signaling signaling NN 1725 1728 has have VBZ 1729 1730 a a DT 1731 1735 role role NN 1736 1738 in in IN 1739 1753 EBV-associated ebv-associated JJ 1754 1766 malignancies malignancy NNS 1766 1767 . . .