0 9 Defective defective JJ 10 23 translocation translocation NN 24 26 of of IN 27 34 protein protein NN 35 41 kinase kinase NNP 42 43 C C NNP 44 46 in in IN 47 66 multidrug-resistant multidrug-resistant JJ 67 72 HL-60 hl-60 NN 73 78 cells cell NNS 79 86 confers confer VBZ 87 88 a a DT 89 99 reversible reversible JJ 100 104 loss loss NN 105 107 of of IN 108 115 phorbol phorbol NN 116 129 ester-induced ester-induced JJ 130 139 monocytic monocytic JJ 140 155 differentiation differentiation NN 155 156 . . . 158 166 Previous previous JJ 167 174 studies study NNS 175 179 have have VBP 180 192 demonstrated demonstrate VBN 193 197 that that IN 198 203 human human JJ 204 209 HL-60 hl-60 NN 210 217 myeloid myeloid JJ 218 226 leukemia leukemia NN 227 232 cells cell NNS 233 246 differentiate differentiate VBP 247 249 in in IN 250 258 response response NN 259 261 to to TO 262 269 phorbol phorbol NN 270 276 esters ester NNS 276 277 . . . 278 282 This this DT 283 288 event event NN 289 291 is be VBZ 292 302 associated associate VBN 303 307 with with IN 308 317 induction induction NN 318 320 of of IN 321 324 the the DT 325 330 c-jun c-jun NN 331 336 early early JJ 337 345 response response NN 346 350 gene gene NN 351 354 and and CC 355 365 appearance appearance NN 366 368 of of IN 369 370 a a DT 371 380 monocytic monocytic JJ 381 390 phenotype phenotype NN 390 391 . . . 392 395 The the DT 396 403 present present JJ 404 411 studies study NNS 412 416 have have VBP 417 425 examined examine VBN 426 429 the the DT 430 437 effects effect NNS 438 440 of of IN 441 461 vincristine-selected vincristine-selected JJ 461 462 , , , 463 472 multidrug multidrug JJ 473 483 resistance resistance NN 484 486 on on IN 487 523 12-O-tetradecanoylphorbol-13-acetate 12-O-tetradecanoylphorbol-13-acetate NNP 524 525 ( ( ( 525 537 TPA)-induced tpa)-induced JJ 538 543 HL-60 HL-60 NNP 544 548 cell cell NN 549 564 differentiation differentiation NN 564 565 . . . 566 569 The the DT 570 577 results result NNS 578 589 demonstrate demonstrate VBP 590 594 that that IN 595 614 multidrug-resistant multidrug-resistant JJ 615 620 HL-60 hl-60 NN 621 626 cells cell NNS 626 627 , , , 628 638 designated designate VBN 639 649 HL-60/vinc HL-60/vinc NNP 649 650 , , , 651 655 fail fail VBP 656 658 to to TO 659 666 respond respond VB 667 669 to to TO 670 673 TPA TPA NNP 674 678 with with IN 679 681 an an DT 682 690 increase increase NN 691 693 in in IN 694 699 c-jun c-jun NN 700 711 transcripts transcript NNS 712 714 or or CC 715 720 other other JJ 721 731 phenotypic phenotypic JJ 732 747 characteristics characteristic NNS 748 750 of of IN 751 760 monocytic monocytic JJ 761 776 differentiation differentiation NN 776 777 . . . 778 780 By by IN 781 789 contrast contrast NN 789 790 , , , 791 800 treatment treatment NN 801 803 of of IN 804 814 HL-60/vinc hl-60/vinc NN 815 820 cells cell NNS 821 825 with with IN 826 833 okadaic okadaic JJ 834 838 acid acid NN 838 839 , , , 840 842 an an DT 843 852 inhibitor inhibitor NN 853 855 of of IN 856 872 serine/threonine serine/threonine NN 873 880 protein protein NN 881 893 phosphatases phosphatas NNS 893 894 , , , 895 902 induces induce VBZ 903 908 c-jun c-jun NN 909 922 transcription transcription NN 922 923 , , , 924 930 growth growth NN 931 937 arrest arrest NN 937 938 , , , 939 942 and and CC 943 953 expression expression NN 954 956 of of IN 957 960 the the DT 961 966 c-fms c-fms NN 967 971 gene gene NN 971 972 . . . 973 980 Studies study NNS 981 985 were be VBD 986 990 also also RB 991 1000 performed perform VBN 1001 1005 with with IN 1006 1008 an an DT 1009 1019 HL-60/vinc HL-60/vinc NNP 1020 1029 revertant revertant NN 1030 1031 ( ( ( 1031 1043 HL-60/vinc/R HL-60/vinc/R NNP 1043 1044 ) ) ) 1045 1049 line line NN 1050 1054 that that WDT 1055 1058 has have VBZ 1059 1067 regained regain VBN 1068 1075 partial partial JJ 1076 1087 sensitivity sensitivity NN 1088 1090 to to TO 1091 1102 vincristine vincristine NN 1102 1103 . . . 1104 1107 The the DT 1108 1115 finding finding NN 1116 1120 that that IN 1121 1133 HL-60/vinc/R HL-60/vinc/R NNP 1134 1139 cells cell NNS 1140 1147 respond respond VBP 1148 1150 to to TO 1151 1154 TPA TPA NNP 1155 1159 with with IN 1160 1169 induction induction NN 1170 1172 of of IN 1173 1174 a a DT 1175 1184 monocytic monocytic JJ 1185 1194 phenotype phenotype NN 1194 1195 , , , 1196 1199 but but CC 1200 1203 not not RB 1204 1209 c-jun c-jun NN 1210 1220 expression expression NN 1220 1221 , , , 1222 1230 suggests suggest VBZ 1231 1235 that that IN 1236 1241 c-jun c-jun NN 1242 1251 induction induction NN 1252 1254 is be VBZ 1255 1258 not not RB 1259 1269 obligatory obligatory JJ 1270 1273 for for IN 1274 1283 monocytic monocytic JJ 1284 1299 differentiation differentiation NN 1299 1300 . . . 1301 1306 Other other JJ 1307 1314 studies study NNS 1315 1322 further further RB 1323 1334 demonstrate demonstrate VBP 1335 1339 that that IN 1340 1343 the the DT 1344 1349 jun-B jun-b NN 1350 1353 and and CC 1354 1359 fra-1 fra-1 NN 1360 1365 genes gene NNS 1366 1369 are be VBP 1370 1377 induced induce VBN 1378 1380 by by IN 1381 1384 TPA TPA NNP 1385 1387 in in IN 1388 1392 both both CC 1393 1403 HL-60/vinc HL-60/vinc NNP 1404 1407 and and CC 1408 1420 HL-60/vinc/R HL-60/vinc/R NNP 1421 1426 cells cell NNS 1426 1427 , , , 1428 1435 whereas whereas IN 1436 1441 c-fos c-fos NN 1442 1452 expression expression NN 1453 1455 is be VBZ 1456 1466 attenuated attenuate VBN 1467 1469 in in IN 1470 1473 the the DT 1474 1484 HL-60/vinc HL-60/vinc NNP 1485 1489 line line NN 1489 1490 . . . 1491 1496 Since since IN 1497 1500 TPA TPA NNP 1501 1510 activates activate VBZ 1511 1518 protein protein NN 1519 1525 kinase kinase NNP 1526 1527 C C NNP 1528 1529 ( ( ( 1529 1532 PKC PKC NNP 1532 1533 ) ) ) 1533 1534 , , , 1535 1537 we we PRP 1538 1546 examined examine VBD 1547 1560 translocation translocation NN 1561 1563 of of IN 1564 1567 PKC PKC NNP 1568 1572 from from IN 1573 1576 the the DT 1577 1584 cytosol cytosol NN 1585 1587 to to TO 1588 1591 the the DT 1592 1600 membrane membrane NN 1601 1609 fraction fraction NN 1609 1610 . . . 1611 1619 Although although IN 1620 1625 HL-60 HL-60 NNP 1626 1629 and and CC 1630 1642 HL-60/vinc/R HL-60/vinc/R NNP 1643 1648 cells cell NNS 1649 1661 demonstrated demonstrate VBD 1662 1675 translocation translocation NN 1676 1678 of of IN 1679 1682 PKC PKC NNP 1683 1691 activity activity NN 1691 1692 , , , 1693 1697 this this DT 1698 1709 subcellular subcellular JJ 1710 1724 redistribution redistribution NN 1725 1728 was be VBD 1729 1741 undetectable undetectable JJ 1742 1744 in in IN 1745 1755 HL-60/vinc hl-60/vinc NN 1756 1761 cells cell NNS 1761 1762 . . . 1763 1771 Activity activity NN 1772 1774 of of IN 1775 1778 the the DT 1779 1796 mitogen-activated mitogen-activated JJ 1797 1804 protein protein NN 1805 1811 kinase kinase NNP 1812 1818 family family NN 1819 1823 with with IN 1824 1834 associated associate VBN 1835 1850 phosphorylation phosphorylation NN 1851 1853 of of IN 1854 1859 c-Jun c-jun NN 1860 1869 Y-peptide Y-peptide NNP 1870 1873 was be VBD 1874 1882 markedly markedly RB 1883 1893 diminished diminish VBN 1894 1896 in in IN 1897 1908 TPA-treated tpa-treated JJ 1909 1919 HL-60/vinc HL-60/vinc NNP 1920 1925 cells cell NNS 1925 1926 , , , 1927 1930 but but CC 1931 1934 not not RB 1935 1937 in in IN 1938 1946 response response NN 1947 1949 to to TO 1950 1957 okadaic okadaic JJ 1958 1962 acid acid NN 1962 1963 . . . 1964 1969 Taken take VBN 1970 1978 together together RB 1978 1979 , , , 1980 1985 these these DT 1986 1994 findings finding NNS 1995 2002 suggest suggest VBP 2003 2007 that that IN 2008 2019 vincristine vincristine NN 2020 2030 resistance resistance NN 2031 2038 confers confer VBZ 2039 2052 insensitivity insensitivity NN 2053 2055 to to TO 2056 2067 TPA-induced tpa-induced JJ 2068 2083 differentiation differentiation NN 2084 2087 and and CC 2088 2091 can can MD 2092 2099 include include VB 2100 2107 defects defect NNS 2108 2110 in in IN 2111 2123 PKC-mediated pkc-mediated JJ 2124 2133 signaling signaling NN 2134 2140 events event NNS 2141 2144 and and CC 2145 2154 induction induction NN 2155 2157 of of IN 2158 2165 jun/fos jun/fos NN 2166 2171 early early JJ 2172 2180 response response NN 2181 2185 gene gene NN 2186 2196 expression expression NN 2196 2197 . . .