0 3 The the DT 4 8 role role NN 9 11 of of IN 12 15 p16 p16 NN 16 18 in in IN 19 22 the the DT 23 36 E2F-dependent e2f-dependent JJ 37 46 thymidine thymidine NN 47 53 kinase kinase NNP 54 64 regulation regulation NN 64 65 . . . 67 70 The the DT 71 75 role role NN 76 78 of of IN 79 90 alterations alteration NNS 91 93 of of IN 94 97 the the DT 98 102 MTS1 mts1 NN 103 108 tumor tumor NN 109 119 suppressor suppressor NN 120 124 gene gene NN 125 127 on on IN 128 138 chromosome chromosome NN 139 143 9p21 9p21 NN 143 144 , , , 145 150 which which WDT 151 158 encodes encode VBZ 159 162 p16 p16 NN 162 163 , , , 164 167 the the DT 168 177 inhibitor inhibitor NN 178 180 of of IN 181 206 cyclin-dependent-kinase-4 cyclin-dependent-kinase-4 NN 207 210 and and CC 211 212 6 6 CD 212 213 , , , 214 216 in in IN 217 230 tumorigenesis tumorigenesis NN 231 233 is be VBZ 234 237 not not RB 238 241 yet yet RB 242 247 clear clear JJ 247 248 . . . 249 264 Phosphorylation phosphorylation NN 265 267 of of IN 268 271 the the DT 272 286 retinoblastoma retinoblastoma NN 287 294 protein protein NN 295 297 by by IN 298 314 cyclin-dependent cyclin-dependent JJ 315 322 kinases kinase NNS 323 324 4 4 CD 325 328 and and CC 329 330 6 6 CD 331 339 prevents prevent VBZ 340 343 its its PRP$ 344 355 interaction interaction NN 356 360 with with IN 361 364 the the DT 365 378 transcription transcription NN 379 385 factor factor NN 386 389 E2F E2F NNP 389 390 , , , 391 396 which which WDT 397 409 subsequently subsequently RB 410 418 promotes promote VBZ 419 422 the the DT 423 433 expression expression NN 434 436 of of IN 437 438 S S NNP 439 444 phase phase NN 445 454 regulated regulated JJ 455 460 genes gene NNS 460 461 , , , 462 466 such such JJ 467 469 as as IN 470 479 thymidine thymidine NN 480 486 kinase kinase NNP 486 487 . . . 488 496 Although although IN 497 498 a a DT 499 503 role role NN 504 506 of of IN 507 510 p16 p16 NN 511 513 in in IN 514 518 this this DT 519 529 regulation regulation NN 530 533 has have VBZ 534 538 been be VBN 539 547 presumed presume VBN 547 548 , , , 549 554 there there EX 555 557 is be VBZ 558 560 no no DT 561 566 proof proof NN 567 569 so so RB 570 573 far far RB 574 578 that that IN 579 583 loss loss NN 584 586 of of IN 587 591 this this DT 592 597 tumor tumor NN 598 608 suppressor suppressor NN 609 613 gene gene NN 614 620 really really RB 621 628 affects affect VBZ 629 641 E2F-mediated e2f-mediated JJ 642 653 regulations regulation NNS 653 654 . . . 655 657 We we PRP 658 670 investigated investigate VBD 671 674 the the DT 675 685 regulation regulation NN 686 688 of of IN 689 698 thymidine thymidine NN 699 705 kinase kinase NNP 706 708 in in IN 709 738 phytohemagglutinin-stimulated phytohemagglutinin-stimulated JJ 739 745 normal normal JJ 746 751 human human JJ 752 763 lymphocytes lymphocyte NNS 764 767 and and CC 768 770 in in IN 771 774 the the DT 775 787 p16-negative p16-negative JJ 788 793 human human JJ 794 799 acute acute JJ 800 813 lymphoblastic lymphoblastic JJ 814 822 leukemia leukemia NN 823 827 cell cell NN 828 833 lines line NNS 833 834 , , , 835 841 MOLT-4 molt-4 NN 842 845 and and CC 846 849 CEM CEM NNP 849 850 . . . 851 859 Compared compare VBN 860 862 to to TO 863 869 normal normal JJ 870 881 lymphocytes lymphocyte NNS 881 882 , , , 883 889 MOLT-4 molt-4 NN 890 893 and and CC 894 897 CEM CEM NNP 898 903 cells cell NNS 904 913 exhibited exhibit VBD 914 916 an an DT 917 924 altered altered JJ 925 929 cell cell NN 930 935 cycle cycle NN 936 946 regulation regulation NN 947 949 of of IN 950 959 thymidine thymidine NN 960 966 kinase kinase NNP 966 967 , , , 968 969 a a DT 970 974 much much RB 975 981 higher high JJR 982 995 intracellular intracellular JJ 996 1004 activity activity NN 1005 1007 of of IN 1008 1012 this this DT 1013 1019 enzyme enzyme NN 1019 1020 , , , 1021 1024 and and CC 1025 1031 higher high JJR 1032 1041 thymidine thymidine NN 1042 1048 kinase kinase NNP 1049 1053 mRNA mRNA NNP 1054 1064 expression expression NN 1064 1065 . . . 1066 1075 Transient transient JJ 1076 1086 expression expression NN 1087 1089 of of IN 1090 1093 p16 p16 NN 1094 1096 in in IN 1097 1103 normal normal JJ 1104 1109 human human JJ 1110 1121 lymphocytes lymphocyte NNS 1122 1128 caused cause VBD 1129 1135 arrest arrest NN 1136 1138 in in IN 1139 1141 G1 G1 NNP 1141 1142 , , , 1143 1146 but but CC 1147 1150 was be VBD 1151 1158 without without IN 1159 1165 effect effect NN 1166 1168 on on IN 1169 1172 the the DT 1173 1177 cell cell NN 1178 1184 growth growth NN 1185 1187 of of IN 1188 1194 MOLT-4 molt-4 NN 1195 1198 and and CC 1199 1202 CEM CEM NNP 1203 1208 cells cell NNS 1208 1209 , , , 1210 1218 although although IN 1219 1222 all all DT 1223 1225 of of IN 1226 1230 them them PRP 1231 1238 express express VBP 1239 1249 functional functional JJ 1250 1264 retinoblastoma retinoblastoma NN 1265 1272 protein protein NN 1272 1273 . . . 1274 1286 Nevertheless nevertheless RB 1286 1287 , , , 1288 1290 in in IN 1291 1294 the the DT 1295 1298 two two CD 1299 1307 leukemia leukemia NN 1308 1312 cell cell NN 1313 1318 lines line NNS 1319 1328 transient transient JJ 1329 1343 overexpression overexpression NN 1344 1346 of of IN 1347 1350 p16 p16 NN 1351 1364 reestablished reestablish VBD 1365 1368 the the DT 1369 1375 normal normal JJ 1376 1386 regulation regulation NN 1387 1389 of of IN 1390 1399 thymidine thymidine NN 1400 1406 kinase kinase NNP 1406 1407 , , , 1408 1418 paralleled parallel VBN 1419 1421 by by IN 1422 1424 an an DT 1425 1433 increase increase NN 1434 1436 of of IN 1437 1440 the the DT 1441 1460 underphosphorylated underphosphorylated JJ 1461 1465 form form NN 1466 1468 of of IN 1469 1483 retinoblastoma retinoblastoma NN 1484 1491 protein protein NN 1492 1495 and and CC 1496 1504 decrease decrease NN 1505 1507 of of IN 1508 1512 free free JJ 1513 1516 E2F e2f NN 1517 1522 bound bind VBD 1523 1525 to to TO 1526 1529 its its PRP$ 1530 1535 motif motif NN 1536 1538 in in IN 1539 1542 the the DT 1543 1552 thymidine thymidine NN 1553 1559 kinase kinase NNP 1560 1568 promoter promoter NN 1568 1569 . . . 1570 1572 We we PRP 1573 1584 demonstrate demonstrate VBP 1585 1589 that that IN 1590 1594 loss loss NN 1595 1597 of of IN 1598 1601 p16 p16 NN 1602 1608 causes cause VBZ 1609 1621 upregulation upregulation NN 1622 1624 of of IN 1625 1629 this this DT 1630 1633 DNA DNA NNP 1634 1643 precursor precursor NN 1644 1651 pathway pathway NN 1652 1658 enzyme enzyme NN 1659 1662 via via IN 1663 1673 activation activation NN 1674 1676 of of IN 1677 1680 E2F E2F NNP 1681 1683 by by IN 1684 1685 a a DT 1686 1695 mechanism mechanism NN 1696 1705 involving involve VBG 1706 1720 retinoblastoma retinoblastoma NN 1721 1728 protein protein NN 1728 1729 . . .