0 3 New new JJ 4 21 immunosuppressive immunosuppressive JJ 22 26 drug drug NN 27 36 PNU156804 pnu156804 NN 37 43 blocks block VBZ 44 58 IL-2-dependent il-2-dependent JJ 59 72 proliferation proliferation NN 73 76 and and CC 77 85 NF-kappa NF-kappa NNP 86 87 B B NNP 88 91 and and CC 92 96 AP-1 ap-1 NN 97 107 activation activation NN 107 108 . . . 110 112 We we PRP 113 116 had have VBD 117 127 previously previously RB 128 133 shown show VBN 134 138 that that IN 139 142 the the DT 143 147 drug drug NN 148 166 undecylprodigiosin undecylprodigiosin NN 167 168 ( ( ( 168 170 UP up NN 170 171 ) ) ) 172 178 blocks block VBZ 179 184 human human JJ 185 195 lymphocyte lymphocyte NN 196 209 proliferation proliferation NN 210 212 in in FW 213 218 vitro vitro FW 218 219 . . . 220 222 We we PRP 223 227 have have VBP 228 231 now now RB 232 244 investigated investigate VBN 245 248 the the DT 249 258 mechanism mechanism NN 259 261 of of IN 262 268 action action NN 269 271 of of IN 272 273 a a DT 274 277 new new JJ 278 286 analogue analogue NN 287 289 of of IN 290 292 UP up NN 292 293 , , , 294 303 PNU156804 PNU156804 NNP 303 304 , , , 305 310 which which WDT 311 316 shows show VBZ 317 318 a a DT 319 323 more more RBR 324 333 favorable favorable JJ 334 342 activity activity NN 343 350 profile profile NN 351 355 than than IN 356 358 UP up NN 359 361 in in IN 362 366 mice mouse NNS 366 367 . . . 368 370 We we PRP 371 382 demonstrate demonstrate VBP 383 387 here here RB 388 392 that that IN 393 396 the the DT 397 407 biological biological JJ 408 414 effect effect NN 415 417 of of IN 418 427 PNU156804 pnu156804 NN 428 430 in in FW 431 436 vitro vitro FW 437 439 is be VBZ 440 457 indistinguishable indistinguishable JJ 458 462 from from IN 463 465 UP up NN 465 466 : : : 467 476 PNU156804 pnu156804 NN 477 483 blocks block VBZ 484 489 human human JJ 490 491 T t NN 492 496 cell cell NN 497 510 proliferation proliferation NN 511 513 in in IN 514 522 mid-late mid-late JJ 523 525 G1 g1 NN 525 526 , , , 527 529 as as IN 530 540 determined determine VBN 541 543 by by IN 544 548 cell cell NN 549 554 cycle cycle NN 555 563 analysis analysis NN 563 564 , , , 565 575 expression expression NN 576 578 of of IN 579 586 cyclins cyclin NNS 586 587 , , , 588 591 and and CC 592 608 cyclin-dependent cyclin-dependent JJ 609 616 kinases kinase NNS 617 620 and and CC 621 635 retinoblastoma retinoblastoma NN 636 651 phosphorylation phosphorylation NN 651 652 . . . 653 655 In in IN 656 664 addition addition NN 664 665 , , , 666 668 we we PRP 669 673 show show VBP 674 678 that that IN 679 688 PNU156804 pnu156804 NN 689 693 does do VBZ 694 697 not not RB 698 703 block block VB 704 717 significantly significantly RB 718 721 the the DT 722 731 induction induction NN 732 734 of of IN 735 741 either either CC 742 746 IL-2 il-2 NN 747 749 or or CC 750 755 IL-2R il-2r NN 756 762 alpha- alpha- NN 763 766 and and CC 767 779 gamma-chains gamma-chain NNS 780 783 but but CC 784 792 inhibits inhibit VBZ 793 807 IL-2-dependent il-2-dependent JJ 808 809 T t NN 810 814 cell cell NN 815 828 proliferation proliferation NN 828 829 . . . 830 832 We we PRP 833 837 have have VBP 838 850 investigated investigate VBN 851 858 several several JJ 859 868 molecular molecular JJ 869 877 pathways pathway NNS 878 882 that that WDT 883 886 are be VBP 887 892 known know VBN 893 895 to to TO 896 898 be be VB 899 908 activated activate VBN 909 911 by by IN 912 916 IL-2 il-2 NN 917 919 in in IN 920 921 T t NN 922 927 cells cell NNS 927 928 . . . 929 931 We we PRP 932 936 show show VBP 937 941 that that IN 942 951 PNU156804 pnu156804 NN 952 956 does do VBZ 957 960 not not RB 961 968 inhibit inhibit VB 969 974 c-myc c-myc NN 975 978 and and CC 979 984 bcl-2 bcl-2 NN 985 989 mRNA mrna NN 990 999 induction induction NN 999 1000 . . . 1001 1003 On on IN 1004 1007 the the DT 1008 1013 other other JJ 1014 1018 hand hand NN 1018 1019 , , , 1020 1029 PNU156804 PNU156804 NNP 1030 1041 efficiently efficiently RB 1042 1050 inhibits inhibit VBZ 1051 1054 the the DT 1055 1065 activation activation NN 1066 1068 of of IN 1069 1072 the the DT 1073 1081 NF-kappa NF-kappa NNP 1082 1083 B B NNP 1084 1087 and and CC 1088 1092 AP-1 ap-1 NN 1093 1106 transcription transcription NN 1107 1114 factors factor NNS 1114 1115 . . . 1116 1125 PNU156804 pnu156804 NN 1126 1136 inhibition inhibition NN 1137 1139 of of IN 1140 1148 NF-kappa NF-kappa NNP 1149 1150 B B NNP 1151 1161 activation activation NN 1162 1164 is be VBZ 1165 1168 due due IN 1169 1171 to to TO 1172 1175 the the DT 1176 1186 inhibition inhibition NN 1187 1189 of of IN 1190 1193 the the DT 1194 1205 degradation degradation NN 1206 1208 of of IN 1209 1210 I i NN 1211 1216 kappa kappa NN 1217 1224 B-alpha B-alpha NNP 1225 1228 and and CC 1229 1230 I i NN 1231 1236 kappa kappa NN 1237 1243 B-beta B-beta NNP 1243 1244 . . . 1245 1254 PNU156804 pnu156804 NN 1255 1261 action action NN 1262 1264 is be VBZ 1265 1275 restricted restricted JJ 1276 1278 to to TO 1279 1283 some some DT 1284 1293 signaling signaling NN 1294 1302 pathways pathway NNS 1302 1303 ; ; : 1304 1306 it it PRP 1307 1311 does do VBZ 1312 1315 not not RB 1316 1322 affect affect VB 1323 1331 NF-kappa NF-kappa NNP 1332 1333 B B NNP 1334 1344 activation activation NN 1345 1347 by by IN 1348 1351 PMA PMA NNP 1352 1354 in in IN 1355 1356 T t NN 1357 1362 cells cell NNS 1363 1366 but but CC 1367 1373 blocks block VBZ 1374 1378 that that DT 1379 1386 induced induce VBN 1387 1389 by by IN 1390 1394 CD40 cd40 NN 1395 1408 cross-linking cross-linking NN 1409 1411 in in IN 1412 1413 B B NNP 1414 1425 lymphocytes lymphocyte NNS 1425 1426 . . . 1427 1429 We we PRP 1430 1438 conclude conclude VBP 1439 1443 that that IN 1444 1447 the the DT 1448 1459 prodigiosin prodigiosin NN 1460 1466 family family NN 1467 1469 of of IN 1470 1488 immunosuppressants immunosuppressant NNS 1489 1491 is be VBZ 1492 1493 a a DT 1494 1497 new new JJ 1498 1504 family family NN 1505 1507 of of IN 1508 1517 molecules molecule NNS 1518 1522 that that WDT 1523 1527 show show VBP 1528 1529 a a DT 1530 1535 novel novel JJ 1536 1542 target target NN 1543 1554 specificity specificity NN 1555 1562 clearly clearly RB 1563 1571 distinct distinct JJ 1572 1576 from from IN 1577 1581 that that DT 1582 1584 of of IN 1585 1590 other other JJ 1591 1608 immunosuppressive immunosuppressive JJ 1609 1614 drugs drug NNS 1615 1619 such such JJ 1620 1622 as as IN 1623 1634 cyclosporin cyclosporin NN 1635 1636 A A NNP 1636 1637 , , , 1638 1643 FK506 FK506 NNP 1643 1644 , , , 1645 1648 and and CC 1649 1658 rapamycin rapamycin NN 1658 1659 . . .