0 9 Oncogenic oncogenic JJ 10 15 forms form NNS 16 18 of of IN 19 25 NOTCH1 notch1 NN 26 33 lacking lack VBG 34 40 either either CC 41 44 the the DT 45 52 primary primary JJ 53 60 binding bind VBG 61 65 site site NN 66 69 for for IN 70 80 RBP-Jkappa RBP-Jkappa NNP 81 83 or or CC 84 91 nuclear nuclear JJ 92 104 localization localization NN 105 114 sequences sequence NNS 115 121 retain retain VBP 122 125 the the DT 126 133 ability ability NN 134 136 to to TO 137 146 associate associate VB 147 151 with with IN 152 162 RBP-Jkappa RBP-Jkappa NNP 163 166 and and CC 167 175 activate activate VBP 176 189 transcription transcription NN 189 190 . . . 192 201 Truncated truncated JJ 202 207 forms form NNS 208 210 of of IN 211 214 the the DT 215 221 NOTCH1 notch1 NN 222 235 transmembrane transmembrane JJ 236 244 receptor receptor NN 245 255 engineered engineer VBN 256 258 to to TO 259 267 resemble resemble VB 268 274 mutant mutant JJ 275 280 forms form NNS 281 283 of of IN 284 290 NOTCH1 NOTCH1 NNP 291 296 found find VBN 297 299 in in IN 300 307 certain certain JJ 308 313 cases case NNS 314 316 of of IN 317 322 human human JJ 323 324 T t NN 325 329 cell cell NN 330 347 leukemia/lymphoma leukemia/lymphoma NN 348 349 ( ( ( 349 354 T-ALL T-ALL NNP 354 355 ) ) ) 356 367 efficiently efficiently RB 368 374 induce induce VBP 375 380 T-ALL t-all NN 381 385 when when WRB 386 395 expressed express VBN 396 398 in in IN 399 402 the the DT 403 407 bone bone NN 408 414 marrow marrow NN 415 417 of of IN 418 422 mice mouse NNS 422 423 . . . 424 430 Unlike unlike IN 431 441 full-sized full-sized JJ 442 448 NOTCH1 notch1 NN 448 449 , , , 450 453 two two CD 454 458 such such JJ 459 468 truncated truncated JJ 469 474 forms form NNS 475 477 of of IN 478 481 the the DT 482 489 protein protein NN 490 496 either either CC 497 504 lacking lack VBG 505 506 a a DT 507 512 major major JJ 513 520 portion portion NN 521 523 of of IN 524 527 the the DT 528 541 extracellular extracellular JJ 542 548 domain domain NN 549 550 ( ( ( 550 556 DeltaE DeltaE NNP 556 557 ) ) ) 558 560 or or CC 561 571 consisting consist VBG 572 576 only only RB 577 579 of of IN 580 583 the the DT 584 597 intracellular intracellular JJ 598 604 domain domain NN 605 606 ( ( ( 606 609 ICN ICN NNP 609 610 ) ) ) 611 615 were be VBD 616 621 found find VBN 622 624 to to TO 625 633 activate activate VB 634 647 transcription transcription NN 648 650 in in IN 651 659 cultured culture VBN 660 665 cells cell NNS 665 666 , , , 667 677 presumably presumably RB 678 685 through through IN 686 696 RBP-Jkappa RBP-Jkappa NNP 697 705 response response NN 706 714 elements element NNS 715 721 within within IN 722 725 DNA DNA NNP 725 726 . . . 727 731 Both both DT 732 741 truncated truncated JJ 742 747 forms form NNS 748 752 also also RB 753 758 bound bind VBD 759 761 to to TO 762 765 the the DT 766 779 transcription transcription NN 780 786 factor factor NN 787 797 RBP-Jkappa RBP-Jkappa NNP 798 800 in in IN 801 809 extracts extract NNS 810 818 prepared prepare VBN 819 823 from from IN 824 829 human human JJ 830 833 and and CC 834 840 murine murine JJ 841 846 T-ALL t-all NN 847 851 cell cell NN 852 857 lines line NNS 857 858 . . . 859 874 Transcriptional transcriptional JJ 875 885 activation activation NN 886 894 required require VBD 895 898 the the DT 899 907 presence presence NN 908 910 of of IN 911 912 a a DT 913 917 weak weak JJ 918 936 RBP-Jkappa-binding rbp-jkappa-binding JJ 937 941 site site NN 942 948 within within IN 949 952 the the DT 953 959 NOTCH1 notch1 NN 960 967 ankyrin ankyrin NN 968 974 repeat repeat NN 975 981 region region NN 982 984 of of IN 985 988 the the DT 989 1002 intracellular intracellular JJ 1003 1009 domain domain NN 1009 1010 . . . 1011 1023 Unexpectedly unexpectedly RB 1023 1024 , , , 1025 1026 a a DT 1027 1033 second second JJ 1033 1034 , , , 1035 1043 stronger strong JJR 1044 1062 RBP-Jkappa-binding rbp-jkappa-binding JJ 1063 1067 site site NN 1067 1068 , , , 1069 1074 which which WDT 1075 1079 lies lie VBZ 1080 1086 within within IN 1087 1090 the the DT 1091 1104 intracellular intracellular JJ 1105 1111 domain domain NN 1112 1117 close close JJ 1118 1120 to to TO 1121 1124 the the DT 1125 1138 transmembrane transmembrane JJ 1139 1145 region region NN 1146 1149 and and CC 1150 1163 significantly significantly RB 1164 1172 augments augment VBZ 1173 1184 association association NN 1185 1189 with with IN 1190 1200 RBP-Jkappa RBP-Jkappa NNP 1200 1201 , , , 1202 1205 was be VBD 1206 1209 not not RB 1210 1216 needed need VBN 1217 1220 for for IN 1221 1232 oncogenesis oncogenesis NN 1233 1235 or or CC 1236 1239 for for IN 1240 1255 transcriptional transcriptional JJ 1256 1266 activation activation NN 1266 1267 . . . 1268 1273 While while IN 1274 1277 ICN ICN NNP 1278 1286 appeared appear VBD 1287 1296 primarily primarily RB 1297 1299 in in IN 1300 1303 the the DT 1304 1311 nucleus nucleus NN 1311 1312 , , , 1313 1319 DeltaE DeltaE NNP 1320 1329 localized localize VBD 1330 1332 to to TO 1333 1344 cytoplasmic cytoplasmic JJ 1345 1348 and and CC 1349 1356 nuclear nuclear JJ 1357 1366 membranes membrane NNS 1366 1367 , , , 1368 1378 suggesting suggest VBG 1379 1383 that that IN 1384 1396 intranuclear intranuclear JJ 1397 1409 localization localization NN 1410 1412 is be VBZ 1413 1416 not not RB 1417 1426 essential essential JJ 1427 1430 for for IN 1431 1442 oncogenesis oncogenesis NN 1443 1445 or or CC 1446 1461 transcriptional transcriptional JJ 1462 1472 activation activation NN 1472 1473 . . . 1474 1476 In in IN 1477 1484 support support NN 1485 1487 of of IN 1488 1492 this this DT 1493 1507 interpretation interpretation NN 1507 1508 , , , 1509 1517 mutation mutation NN 1518 1520 of of IN 1521 1529 putative putative JJ 1530 1537 nuclear nuclear JJ 1538 1550 localization localization NN 1551 1560 sequences sequence NNS 1561 1570 decreased decrease VBD 1571 1578 nuclear nuclear JJ 1579 1591 localization localization NN 1592 1595 and and CC 1596 1605 increased increase VBD 1606 1621 transcriptional transcriptional JJ 1622 1632 activation activation NN 1633 1635 by by IN 1636 1650 membrane-bound membrane-bound JJ 1651 1657 DeltaE deltae NN 1657 1658 . . . 1659 1674 Transcriptional transcriptional JJ 1675 1685 activation activation NN 1686 1688 by by IN 1689 1693 this this DT 1694 1700 mutant mutant JJ 1701 1705 form form NN 1706 1708 of of IN 1709 1723 membrane-bound membrane-bound JJ 1724 1730 DeltaE deltae NN 1731 1734 was be VBD 1735 1748 approximately approximately RB 1749 1759 equivalent equivalent JJ 1760 1762 to to TO 1763 1767 that that DT 1768 1776 produced produce VBN 1777 1779 by by IN 1780 1792 intranuclear intranuclear JJ 1793 1796 ICN icn NN 1796 1797 . . . 1798 1803 These these DT 1804 1808 data datum NNS 1809 1812 are be VBP 1813 1817 most most RBS 1818 1828 consistent consistent JJ 1829 1833 with with IN 1834 1840 NOTCH1 notch1 NN 1841 1852 oncogenesis oncogenesis NN 1853 1856 and and CC 1857 1872 transcriptional transcriptional JJ 1873 1883 activation activation NN 1884 1889 being be VBG 1890 1901 independent independent JJ 1902 1904 of of IN 1905 1916 association association NN 1917 1921 with with IN 1922 1932 RBP-Jkappa RBP-Jkappa NNP 1933 1935 at at IN 1936 1944 promoter promoter NN 1945 1950 sites site NNS 1950 1951 . . .