0 3 The the DT 4 35 Megakaryocyte/Platelet-specific megakaryocyte/platelet-specific JJ 36 44 enhancer enhancer NN 45 47 of of IN 48 51 the the DT 52 63 alpha2beta1 alpha2beta1 NN 64 72 integrin integrin NN 73 77 gene gene NN 77 78 : : : 79 82 two two CD 83 89 tandem tandem JJ 90 93 AP1 ap1 NN 94 99 sites site NNS 100 103 and and CC 104 107 the the DT 108 125 mitogen-activated mitogen-activated JJ 126 133 protein protein NN 134 140 kinase kinase NNP 141 150 signaling signaling NN 151 158 cascade cascade NN 158 159 . . . 161 164 The the DT 165 176 alpha2beta1 alpha2beta1 NN 177 185 integrin integrin NN 185 186 , , , 187 188 a a DT 189 197 collagen collagen NN 198 206 receptor receptor NN 207 209 on on IN 210 219 platelets platelet NNS 220 223 and and CC 224 238 megakaryocytes megakaryocyte NNS 238 239 , , , 240 242 is be VBZ 243 251 required require VBN 252 255 for for IN 256 262 normal normal JJ 263 271 platelet platelet NN 272 280 function function NN 280 281 . . . 282 297 Transcriptional transcriptional JJ 298 308 regulation regulation NN 309 311 of of IN 312 315 the the DT 316 322 alpha2 alpha2 NN 323 331 integrin integrin NN 332 336 gene gene NN 337 339 in in IN 340 345 cells cell NNS 346 356 undergoing undergo VBG 357 371 megakaryocytic megakaryocytic JJ 372 387 differentiation differentiation NN 388 396 requires require VBZ 397 398 a a DT 399 403 core core NN 404 412 promoter promoter NN 413 420 between between IN 421 423 bp bp NN 424 427 -30 -30 CD 428 431 and and CC 432 435 -92 -92 CD 435 436 , , , 437 438 a a DT 439 447 silencer silencer NN 448 455 between between IN 456 458 bp bp NN 459 462 -92 -92 CD 463 466 and and CC 467 471 -351 -351 CD 471 472 , , , 473 476 and and CC 477 491 megakaryocytic megakaryocytic JJ 492 501 enhancers enhancer NNS 502 504 in in IN 505 508 the the DT 509 515 distal distal JJ 516 517 5 5 CD 517 518 ’ ' SYM 519 524 flank flank NN 524 525 . . . 526 528 We we PRP 529 533 have have VBP 534 537 now now RB 538 548 identified identify VBN 549 550 a a DT 551 557 229-bp 229-bp JJ 558 564 region region NN 565 567 of of IN 568 571 the the DT 572 578 distal distal JJ 579 580 5 5 CD 580 581 ’ ' SYM 582 587 flank flank NN 588 590 of of IN 591 594 the the DT 595 601 alpha2 alpha2 NN 602 610 integrin integrin NN 611 615 gene gene NN 616 624 required require VBN 625 628 for for IN 629 639 high-level high-level JJ 640 648 enhancer enhancer NN 649 657 activity activity NN 658 660 in in IN 661 666 cells cell NNS 667 671 with with IN 672 686 megakaryocytic megakaryocytic JJ 687 695 features feature NNS 695 696 . . . 697 700 Two two CD 701 707 tandem tandem JJ 708 711 AP1 ap1 NN 712 719 binding binding NN 720 725 sites site NNS 726 730 with with IN 731 735 dyad dyad NN 736 744 symmetry symmetry NN 745 748 are be VBP 749 757 required require VBN 758 761 for for IN 762 770 enhancer enhancer NN 771 779 activity activity NN 780 783 and and CC 784 787 for for IN 788 799 DNA-protein dna-protein JJ 800 807 complex complex NN 808 817 formation formation NN 818 822 with with IN 823 830 members member NNS 831 833 of of IN 834 837 the the DT 838 849 c-fos/c-jun c-fos/c-jun NN 850 856 family family NN 856 857 . . . 858 861 The the DT 862 873 requirement requirement NN 874 877 for for IN 878 881 AP1 ap1 NN 882 892 activation activation NN 893 902 suggested suggest VBD 903 904 a a DT 905 909 role role NN 910 913 for for IN 914 917 the the DT 918 935 mitogen-activated mitogen-activated JJ 936 943 protein protein NN 944 950 kinase kinase NNP 951 952 ( ( ( 952 956 MAPK MAPK NNP 956 957 ) ) ) 958 967 signaling signaling NN 968 975 pathway pathway NN 976 978 in in IN 979 989 regulating regulate VBG 990 996 alpha2 alpha2 NN 997 1005 integrin integrin NN 1006 1010 gene gene NN 1011 1021 expression expression NN 1021 1022 . . . 1023 1033 Inhibition Inhibition NNP 1034 1036 of of IN 1037 1040 the the DT 1041 1044 MAP MAP NNP 1045 1051 kinase kinase NNP 1052 1059 cascade cascade NN 1060 1064 with with IN 1065 1072 PD98059 PD98059 NNP 1072 1073 , , , 1074 1075 a a DT 1076 1084 specific specific JJ 1085 1094 inhibitor inhibitor NN 1095 1097 of of IN 1098 1102 MAPK MAPK NNP 1103 1109 kinase kinase NNP 1110 1111 1 1 CD 1111 1112 , , , 1113 1122 prevented prevent VBD 1123 1126 the the DT 1127 1137 expression expression NN 1138 1140 of of IN 1141 1144 the the DT 1145 1151 alpha2 alpha2 NN 1152 1160 integrin integrin NN 1161 1168 subunit subunit NN 1169 1171 in in IN 1172 1177 cells cell NNS 1178 1185 induced induce VBN 1186 1188 to to TO 1189 1195 become become VB 1196 1210 megakaryocytic megakaryocytic JJ 1210 1211 . . . 1212 1214 We we PRP 1215 1222 provide provide VBP 1223 1224 a a DT 1225 1230 model model NN 1231 1233 of of IN 1234 1248 megakaryocytic megakaryocytic JJ 1249 1264 differentiation differentiation NN 1265 1267 in in IN 1268 1273 which which WDT 1274 1284 expression expression NN 1285 1287 of of IN 1288 1291 the the DT 1292 1298 alpha2 alpha2 NN 1299 1307 integrin integrin NN 1308 1312 gene gene NN 1313 1321 requires require VBZ 1322 1331 signaling signaling NN 1332 1335 via via IN 1336 1339 the the DT 1340 1343 MAP MAP NNP 1344 1350 kinase kinase NNP 1351 1358 pathway pathway NN 1359 1361 to to TO 1362 1370 activate activate VB 1371 1374 two two CD 1375 1381 tandem tandem JJ 1382 1385 AP1 ap1 NN 1386 1393 binding binding NN 1394 1399 sites site NNS 1400 1402 in in IN 1403 1406 the the DT 1407 1413 alpha2 alpha2 NN 1414 1422 integrin integrin NN 1423 1431 enhancer enhancer NN 1431 1432 . . .