0 8 Tyrosine Tyrosine NNP 9 15 kinase kinase NNP 16 19 and and CC 20 34 cAMP-dependent camp-dependent JJ 35 42 protein protein NN 43 49 kinase kinase NNP 50 60 activities activity NNS 61 63 in in IN 64 78 CD40-activated cd40-activated JJ 79 84 human human JJ 85 86 B B NNP 87 98 lymphocytes lymphocyte NNS 98 99 . . . 101 103 In in FW 104 109 vitro vitro FW 109 110 , , , 111 116 human human JJ 117 118 B B NNP 119 130 lymphocytes lymphocyte NNS 131 138 undergo undergo VBP 139 148 long-term long-term JJ 149 162 proliferation proliferation NN 163 167 when when WRB 168 177 activated activate VBN 178 185 through through IN 186 190 CD40 CD40 NNP 190 191 , , , 192 193 a a DT 194 201 protein protein NN 202 211 expressed express VBN 212 214 on on IN 215 220 their their PRP$ 221 225 cell cell NN 226 233 surface surface NN 233 234 . . . 235 238 The the DT 239 245 nature nature NN 246 248 of of IN 249 263 CD40-dependent cd40-dependent JJ 264 271 signals signal NNS 272 274 in in IN 275 288 proliferating proliferate VBG 289 294 fresh fresh JJ 295 300 human human JJ 301 313 Epstein-Barr epstein-barr JJ 314 328 virus-negative virus-negative JJ 329 330 B B NNP 331 342 lymphocytes lymphocyte NNS 343 345 is be VBZ 346 355 currently currently RB 356 363 unknown unknown JJ 363 364 . . . 365 367 In in IN 368 372 this this DT 373 378 study study NN 378 379 , , , 380 381 a a DT 382 396 CD40-dependent cd40-dependent JJ 397 398 B B NNP 399 403 cell cell NN 404 411 culture culture NN 412 418 system system NN 419 422 was be VBD 423 427 used use VBN 428 430 to to TO 431 438 examine examine VB 439 442 the the DT 443 447 role role NN 448 450 of of IN 451 460 different different JJ 461 467 signal signal NN 468 480 transduction transduction NN 481 489 elements element NNS 489 490 . . . 491 498 Protein protein NN 499 505 kinase kinase NNP 506 507 C C NNP 508 509 ( ( ( 509 512 PKC PKC NNP 512 513 ) ) ) 514 523 depletion depletion NN 524 533 generated generate VBN 534 536 by by IN 537 538 a a DT 539 548 long-term long-term JJ 549 556 phorbol phorbol NN 557 559 12 12 CD 560 569 myristate myristate NN 570 580 13-acetate 13-acetate NN 581 590 treatment treatment NN 591 594 had have VBD 595 599 weak weak JJ 600 607 effects effect NNS 608 610 on on IN 611 624 proliferation proliferation NN 624 625 . . . 626 632 Rather rather RB 632 633 , , , 634 642 tyrosine tyrosine NN 643 658 phosphorylation phosphorylation NN 659 662 was be VBD 663 668 shown show VBN 669 671 to to TO 672 674 be be VB 675 683 directly directly RB 684 692 involved involve VBN 693 695 in in IN 696 705 mediating mediate VBG 706 720 CD40-dependent cd40-dependent JJ 721 728 signals signal NNS 728 729 . . . 730 733 The the DT 734 737 use use NN 738 740 of of IN 741 744 the the DT 745 752 protein protein NN 753 761 tyrosine tyrosine NN 762 768 kinase kinase NNP 769 770 ( ( ( 770 783 PTK)-specific ptk)-specific JJ 784 793 inhibitor inhibitor NN 794 804 herbimycin herbimycin NN 805 806 A a NN 807 819 dramatically dramatically RB 820 829 decreased decrease VBD 830 838 cellular cellular JJ 839 852 proliferation proliferation NN 853 860 without without IN 861 869 altering alter VBG 870 873 the the DT 874 882 activity activity NN 883 885 of of IN 886 889 the the DT 890 895 human human JJ 896 912 immunodeficiency immunodeficiency NN 913 920 virus-1 virus-1 NN 921 925 long long JJ 926 934 terminal terminal JJ 935 941 repeat repeat NN 942 943 ( ( ( 943 948 HIV-1 HIV-1 NNP 949 952 LTR LTR NNP 952 953 ) ) ) 953 954 , , , 955 956 a a DT 957 965 promoter promoter NN 966 973 largely largely RB 974 983 dependent dependent JJ 984 986 on on IN 987 990 the the DT 991 998 binding binding NN 999 1001 of of IN 1002 1009 nuclear nuclear JJ 1010 1016 factor factor NN 1017 1022 kappa kappa NN 1023 1024 B B NNP 1025 1026 ( ( ( 1026 1029 NF- nf- NF- 1030 1035 kappa kappa NN 1036 1037 B B NNP 1037 1038 ) ) ) 1038 1039 . . . 1040 1042 In in IN 1043 1051 contrast contrast NN 1051 1052 , , , 1053 1056 the the DT 1057 1071 cAMP-dependent camp-dependent JJ 1072 1079 protein protein NN 1080 1086 kinase kinase NNP 1087 1095 specific specific JJ 1096 1105 inhibitor inhibitor NN 1106 1110 H-89 h-89 NN 1111 1118 totally totally RB 1119 1128 inhibited inhibit VBD 1129 1134 HIV-1 HIV-1 NNP 1135 1138 LTR LTR NNP 1139 1147 activity activity NN 1148 1150 at at IN 1151 1152 a a DT 1153 1166 concentration concentration NN 1167 1169 as as RB 1170 1173 low low JJ 1174 1176 as as IN 1177 1180 100 100 CD 1181 1183 nM nm NN 1184 1191 without without IN 1192 1201 affecting affect VBG 1202 1210 cellular cellular JJ 1211 1224 proliferation proliferation NN 1224 1225 . . . 1226 1241 Electrophoretic electrophoretic JJ 1242 1250 mobility mobility NN 1251 1256 shift shift NN 1257 1262 assay assay NN 1263 1264 ( ( ( 1264 1268 EMSA EMSA NNP 1268 1269 ) ) ) 1270 1273 and and CC 1274 1284 supershift supershift NN 1285 1290 assay assay NN 1291 1296 using use VBG 1297 1299 an an DT 1300 1308 NF-kappa NF-kappa NNP 1309 1310 B B NNP 1311 1318 binding binding NN 1319 1327 sequence sequence NN 1328 1332 from from IN 1333 1336 the the DT 1337 1342 kappa kappa NN 1343 1348 light light JJ 1349 1354 chain chain NN 1355 1357 as as IN 1358 1359 a a DT 1360 1365 probe probe NN 1365 1366 , , , 1367 1375 revealed reveal VBD 1376 1380 that that IN 1381 1385 both both CC 1386 1389 p65 p65 NN 1390 1391 ( ( ( 1391 1395 RelA RelA NNP 1395 1396 ) ) ) 1397 1400 and and CC 1401 1406 c-Rel c-rel NN 1407 1411 were be VBD 1412 1419 present present JJ 1420 1422 in in IN 1423 1438 CD40-stimulated cd40-stimulated JJ 1439 1440 B B NNP 1441 1446 cells cell NNS 1446 1447 . . . 1448 1453 While while IN 1454 1457 PKC PKC NNP 1458 1467 depletion depletion NN 1468 1471 did do VBD 1472 1475 not not RB 1476 1481 alter alter VB 1482 1485 the the DT 1486 1494 NF-kappa NF-kappa NNP 1495 1496 B B NNP 1497 1502 level level NN 1502 1503 , , , 1504 1513 treatment treatment NN 1514 1516 of of IN 1517 1518 B B NNP 1519 1530 lymphocytes lymphocyte NNS 1531 1535 with with IN 1536 1540 H-89 H-89 NNP 1541 1543 or or CC 1544 1554 herbimycin herbimycin NN 1555 1556 A a NN 1557 1565 provoked provoke VBD 1566 1567 a a DT 1568 1576 decrease decrease NN 1577 1579 in in IN 1580 1583 the the DT 1584 1592 NF-kappa NF-kappa NNP 1593 1594 B B NNP 1595 1600 level level NN 1600 1601 . . . 1602 1607 These these DT 1608 1620 observations observation NNS 1621 1630 establish establish VBP 1631 1634 the the DT 1635 1645 importance importance NN 1646 1648 of of IN 1649 1658 different different JJ 1659 1665 signal signal NN 1666 1677 transducing transducing NN 1678 1686 pathways pathway NNS 1687 1694 leading lead VBG 1695 1697 to to TO 1698 1702 CD40 CD40 NNP 1703 1713 activation activation NN 1714 1716 of of IN 1717 1718 B B NNP 1719 1730 lymphocytes lymphocyte NNS 1730 1731 . . .