0 15 Transcriptional transcriptional JJ 16 19 and and CC 20 39 posttranscriptional posttranscriptional JJ 40 50 regulation regulation NN 51 53 of of IN 54 63 erythroid erythroid JJ 64 68 gene gene NN 69 79 expression expression NN 80 82 in in IN 83 104 anthracycline-induced anthracycline-induced JJ 105 120 differentiation differentiation NN 121 123 of of IN 124 129 human human JJ 130 145 erythroleukemic erythroleukemic JJ 146 151 cells cell NNS 151 152 . . . 154 167 Aclacinomycin Aclacinomycin NNP 168 169 ( ( ( 169 173 ACLA ACLA NNP 173 174 ) ) ) 175 178 and and CC 179 190 doxorubicin doxorubicin NN 191 192 ( ( ( 192 195 DOX DOX NNP 195 196 ) ) ) 197 201 were be VBD 202 206 used use VBN 207 209 at at IN 210 218 subtoxic subtoxic JJ 219 233 concentrations concentration NNS 234 236 to to TO 237 243 induce induce VB 244 253 erythroid erythroid JJ 254 269 differentiation differentiation NN 270 272 in in IN 273 276 the the DT 277 282 human human JJ 283 291 leukemic leukemic JJ 292 296 cell cell NN 297 301 line line NN 302 306 K562 k562 NN 306 307 . . . 308 312 Cell cell NN 313 330 hemoglobinization hemoglobinization NN 331 334 was be VBD 335 346 accompanied accompany VBN 347 349 by by IN 350 353 the the DT 354 363 increased increase VBN 364 374 expression expression NN 375 377 of of IN 378 383 genes gene NNS 384 392 encoding encode VBG 393 405 gamma-globin gamma-globin NN 406 409 and and CC 410 425 porphobilinogen porphobilinogen NN 426 435 deaminase deaminase NNP 436 437 ( ( ( 437 441 PBGD PBGD NNP 441 442 ) ) ) 442 443 , , , 444 446 an an DT 447 453 enzyme enzyme NN 454 456 of of IN 457 461 heme heme NN 462 471 synthesis synthesis NN 471 472 . . . 473 475 By by IN 476 481 using use VBG 482 488 run-on run-on JJ 489 495 assays assay NNS 495 496 , , , 497 501 ACLA ACLA NNP 502 505 was be VBD 506 511 shown show VBN 512 514 to to TO 515 521 induce induce VB 522 524 an an DT 525 536 enhancement enhancement NN 537 539 of of IN 540 543 the the DT 544 557 transcription transcription NN 558 560 of of IN 561 570 erythroid erythroid JJ 571 576 genes gene NNS 576 577 , , , 578 587 including include VBG 588 600 gamma-globin gamma-globin NN 600 601 , , , 602 606 PBGD PBGD NNP 606 607 , , , 608 622 erythropoietin erythropoietin NN 623 631 receptor receptor NN 631 632 , , , 633 636 and and CC 637 643 GATA-1 gata-1 NN 644 657 transcription transcription NN 658 664 factor factor NN 664 665 . . . 666 668 In in IN 669 677 contrast contrast NN 677 678 , , , 679 681 in in IN 682 693 DOX-treated dox-treated JJ 694 699 cells cell NNS 699 700 , , , 701 704 the the DT 705 718 transcription transcription NN 719 723 rate rate NN 724 726 of of IN 727 732 these these DT 733 738 genes gene NNS 739 742 was be VBD 743 752 unchanged unchanged JJ 753 755 in in IN 756 766 comparison comparison NN 767 771 with with IN 772 779 control control NN 780 785 cells cell NNS 785 786 . . . 787 789 In in IN 790 798 addition addition NN 798 799 , , , 800 810 inhibition inhibition NN 811 813 of of IN 814 818 mRNA mrna NN 819 828 synthesis synthesis NN 829 833 with with IN 834 845 actinomycin actinomycin NN 846 847 D D NNP 848 857 indicated indicate VBD 858 862 that that IN 863 866 DOX DOX NNP 867 874 induced induce VBD 875 877 an an DT 878 887 increased increase VBN 888 897 stability stability NN 898 900 of of IN 901 905 PBGD PBGD NNP 906 909 and and CC 910 916 GATA-1 gata-1 NN 917 922 mRNAs mrna NNS 922 923 , , , 924 931 whereas whereas IN 932 936 ACLA ACLA NNP 937 940 did do VBD 941 944 not not RB 945 951 affect affect VB 952 955 the the DT 956 966 half-lives half-live NNS 967 969 of of IN 970 975 these these DT 976 981 mRNAs mrna NNS 981 982 . . . 983 990 Because because IN 991 994 the the DT 995 1003 increase increase NN 1004 1006 in in IN 1007 1016 erythroid erythroid JJ 1017 1021 mRNA mrna NN 1022 1034 steady-state steady-state JJ 1035 1040 level level NN 1041 1043 in in IN 1044 1065 anthracycline-treated anthracycline-treated JJ 1066 1071 cells cell NNS 1072 1075 was be VBD 1076 1085 inhibited inhibit VBN 1086 1088 by by IN 1089 1102 cycloheximide cycloheximide NN 1102 1103 , , , 1104 1108 this this DT 1109 1117 suggests suggest VBZ 1118 1122 that that IN 1123 1138 transcriptional transcriptional JJ 1139 1149 activation activation NN 1150 1152 in in IN 1153 1165 ACLA-treated acla-treated JJ 1166 1171 cells cell NNS 1172 1175 and and CC 1176 1180 mRNA mrna NN 1181 1194 stabilization stabilization NN 1195 1197 in in IN 1198 1209 DOX-treated dox-treated JJ 1210 1215 cells cell NNS 1216 1220 were be VBD 1221 1230 dependent dependent JJ 1231 1233 on on IN 1234 1236 de de FW 1237 1241 novo novo FW 1242 1249 protein protein NN 1250 1259 synthesis synthesis NN 1259 1260 . . . 1261 1268 Finally finally RB 1268 1269 , , , 1270 1276 GATA-1 gata-1 NN 1277 1284 protein protein NN 1285 1290 level level NN 1291 1294 was be VBD 1295 1300 shown show VBN 1301 1303 to to TO 1304 1306 be be VB 1307 1316 increased increase VBN 1317 1319 in in IN 1320 1332 ACLA-treated acla-treated JJ 1333 1336 but but CC 1337 1340 not not RB 1341 1343 in in IN 1344 1355 DOX-treated dox-treated JJ 1356 1361 cells cell NNS 1361 1362 . . . 1363 1368 These these DT 1369 1372 two two CD 1373 1387 anthracyclines anthracycline NNS 1387 1388 , , , 1389 1397 although although IN 1398 1405 closely closely RB 1406 1413 related related JJ 1414 1416 in in IN 1417 1422 their their PRP$ 1423 1433 structures structure NNS 1433 1434 , , , 1435 1443 appeared appear VBD 1444 1446 to to TO 1447 1450 act act VB 1451 1453 as as IN 1454 1469 differentiation differentiation NN 1470 1478 inducers inducer NNS 1479 1481 by by IN 1482 1490 distinct distinct JJ 1491 1501 mechanisms mechanism NNS 1501 1502 . . . 1503 1509 Indeed indeed RB 1509 1510 , , , 1511 1520 erythroid erythroid JJ 1521 1525 gene gene NN 1526 1536 expression expression NN 1537 1540 was be VBD 1541 1553 demonstrated demonstrate VBN 1554 1556 to to TO 1557 1559 be be VB 1560 1569 regulated regulate VBN 1570 1587 transcriptionally transcriptionally RB 1588 1590 by by IN 1591 1595 ACLA ACLA NNP 1596 1599 and and CC 1600 1606 mainly mainly RB 1607 1628 posttranscriptionally posttranscriptionally RB 1629 1631 by by IN 1632 1635 DOX DOX NNP 1635 1636 . . .