0 4 GABP GABP NNP 5 12 factors factor NNS 13 17 bind bind VBP 18 20 to to TO 21 22 a a DT 23 29 distal distal JJ 30 41 interleukin interleukin NN 42 43 2 2 CD 44 45 ( ( ( 45 49 IL-2 il-2 NN 49 50 ) ) ) 51 59 enhancer enhancer NN 60 63 and and CC 64 74 contribute contribute VBP 75 77 to to TO 78 92 c-Raf-mediated c-raf-mediated JJ 93 101 increase increase NN 102 104 in in IN 105 109 IL-2 il-2 NN 110 119 induction induction NN 119 120 . . . 122 132 Triggering triggering NN 133 135 of of IN 136 139 the the DT 140 146 T-cell t-cell NN 147 159 receptor-CD3 receptor-cd3 NN 160 167 complex complex NN 168 177 activates activate VBZ 178 181 two two CD 182 187 major major JJ 188 194 signal signal NN 195 203 cascades cascade NNS 204 206 in in IN 207 208 T t NN 209 220 lymphocytes lymphocyte NNS 220 221 , , , 222 223 ( ( ( 223 224 i i LS 224 225 ) ) ) 226 240 Ca2+-dependent ca2+-dependent JJ 241 247 signal signal NN 248 256 cascades cascade NNS 257 260 and and CC 261 262 ( ( ( 262 264 ii ii LS 264 265 ) ) ) 266 273 protein protein NN 274 280 kinase kinase NNP 281 289 cascades cascade NNS 289 290 . . . 291 295 Both both DT 296 302 signal signal NN 303 311 cascades cascade NNS 312 322 contribute contribute VBP 323 325 to to TO 326 329 the the DT 330 339 induction induction NN 340 342 of of IN 343 346 the the DT 347 358 interleukin interleukin NN 359 360 2 2 CD 361 362 ( ( ( 362 366 IL-2 il-2 NN 366 367 ) ) ) 368 372 gene gene NN 373 379 during during IN 380 386 T-cell t-cell NN 387 397 activation activation NN 397 398 . . . 399 408 Prominent prominent JJ 409 416 protein protein NN 417 423 kinase kinase NNP 424 432 cascades cascade NNS 433 436 are be VBP 437 442 those those DT 443 447 that that WDT 448 456 activate activate VBP 457 474 mitogen-activated mitogen-activated JJ 475 482 protein protein NN 483 484 ( ( ( 484 487 MAP MAP NNP 487 488 ) ) ) 489 496 kinases kinase NNS 496 497 . . . 498 500 We we PRP 501 505 show show VBP 506 510 here here RB 511 515 that that IN 516 521 c-Raf c-raf NN 521 522 , , , 523 528 which which WDT 529 531 is be VBZ 532 534 at at IN 535 538 the the DT 539 543 helm helm NN 544 546 of of IN 547 550 the the DT 551 558 classic classic JJ 559 566 MAP-Erk MAP-Erk NNP 567 574 cascade cascade NN 574 575 , , , 576 587 contributes contribute VBZ 588 590 to to TO 591 595 IL-2 il-2 NN 596 605 induction induction NN 606 613 through through IN 614 615 a a DT 616 622 distal distal JJ 623 631 enhancer enhancer NN 632 639 element element NN 640 648 spanning span VBG 649 652 the the DT 653 664 nucleotides nucleotide NNS 665 669 from from IN 670 679 positions position NNS 680 684 -502 -502 CD 685 687 to to TO 688 692 -413 -413 CD 693 695 in in IN 696 701 front front NN 702 704 of of IN 705 708 the the DT 709 724 transcriptional transcriptional JJ 725 730 start start NN 731 735 site site NN 736 738 of of IN 739 742 the the DT 743 747 IL-2 il-2 NN 748 752 gene gene NN 752 753 . . . 754 763 Induction Induction NNP 764 766 of of IN 767 771 this this DT 772 778 distal distal JJ 779 783 IL-2 il-2 NN 784 792 enhancer enhancer NN 793 800 differs differ VBZ 801 805 from from IN 806 815 induction induction NN 816 818 of of IN 819 822 the the DT 823 831 proximal proximal JJ 832 836 IL-2 il-2 NN 837 854 promoter-enhancer promoter-enhancer NN 854 855 , , , 856 861 since since IN 862 864 it it PRP 865 867 is be VBZ 868 875 induced induce VBN 876 878 by by IN 879 886 phorbol phorbol NN 887 893 esters ester NNS 894 899 alone alone RB 900 903 and and CC 904 915 independent independent JJ 916 920 from from IN 921 925 Ca2+ ca2+ NN 926 933 signals signal NNS 933 934 . . . 935 937 In in IN 938 949 DNA-protein dna-protein JJ 950 957 binding binding NN 958 965 studies study NNS 965 966 , , , 967 969 we we PRP 970 978 detected detect VBD 979 982 the the DT 983 990 binding binding NN 991 993 of of IN 994 1007 transcription transcription NN 1008 1015 factors factor NNS 1016 1020 GABP GABP NNP 1021 1026 alpha alpha NN 1027 1030 and and CC 1031 1036 -beta -beta NN 1037 1039 to to TO 1040 1041 a a DT 1042 1046 dyad dyad NN 1047 1055 symmetry symmetry NN 1056 1063 element element NN 1064 1065 ( ( ( 1065 1068 DSE DSE NNP 1068 1069 ) ) ) 1070 1072 of of IN 1073 1076 the the DT 1077 1083 distal distal JJ 1084 1092 enhancer enhancer NN 1092 1093 , , , 1094 1099 which which WDT 1100 1102 is be VBZ 1103 1109 formed form VBN 1110 1112 by by IN 1113 1124 palindromic palindromic JJ 1125 1132 binding bind VBG 1133 1138 sites site NNS 1139 1141 of of IN 1142 1150 Ets-like ets-like JJ 1151 1158 factors factor NNS 1158 1159 . . . 1160 1172 Introduction introduction NN 1173 1175 of of IN 1176 1181 point point NN 1182 1191 mutations mutation NNS 1192 1203 suppressing suppress VBG 1204 1208 GABP GABP NNP 1209 1216 binding binding NN 1217 1219 to to TO 1220 1223 the the DT 1224 1227 DSE DSE NNP 1228 1238 interfered interfere VBD 1239 1243 with with IN 1244 1247 the the DT 1248 1257 induction induction NN 1258 1260 of of IN 1261 1264 the the DT 1265 1271 distal distal JJ 1272 1280 enhancer enhancer NN 1281 1284 and and CC 1285 1288 the the DT 1289 1295 entire entire JJ 1296 1300 IL-2 il-2 NN 1301 1318 promoter-enhancer promoter-enhancer NN 1318 1319 , , , 1320 1325 while while IN 1326 1340 overexpression overexpression NN 1341 1343 of of IN 1344 1348 both both DT 1349 1353 GABP GABP NNP 1354 1361 factors factor NNS 1362 1370 enhanced enhance VBD 1371 1374 the the DT 1375 1379 IL-2 il-2 NN 1380 1397 promoter-enhancer promoter-enhancer JJ 1398 1407 induction induction NN 1407 1408 . . . 1409 1423 Overexpression Overexpression NNP 1424 1426 of of IN 1427 1430 BXB BXB NNP 1430 1431 , , , 1432 1433 a a DT 1434 1446 constitutive constitutive JJ 1447 1453 active active JJ 1454 1461 version version NN 1462 1464 of of IN 1465 1470 c-Raf c-raf NN 1470 1471 , , , 1472 1475 and and CC 1476 1478 of of IN 1479 1486 further further JJ 1487 1494 members member NNS 1495 1497 of of IN 1498 1501 the the DT 1502 1513 Ras-Raf-Erk Ras-Raf-Erk NNP 1514 1520 signal signal NN 1521 1528 cascade cascade NN 1529 1536 exerted exert VBD 1537 1539 an an DT 1540 1548 increase increase NN 1549 1551 of of IN 1552 1565 GABP-mediated gabp-mediated JJ 1566 1583 promoter-enhancer promoter-enhancer JJ 1584 1593 induction induction NN 1593 1594 . . . 1595 1597 In in IN 1598 1609 conjunction conjunction NN 1610 1614 with with IN 1615 1625 previously previously RB 1626 1635 published publish VBN 1636 1640 data datum NNS 1641 1643 on on IN 1644 1657 c-Raf-induced c-raf-induced JJ 1658 1673 phosphorylation phosphorylation NN 1674 1676 of of IN 1677 1681 GABP GABP NNP 1682 1689 factors factor NNS 1690 1691 ( ( ( 1691 1698 E.Flory E.Flory NNP 1698 1699 , , , 1700 1702 A. A. NNP 1703 1712 Hoffmeyer Hoffmeyer NNP 1712 1713 , , , 1714 1721 U.Smola U.Smola NNP 1721 1722 , , , 1723 1731 U.R.Rapp U.R.Rapp NNP 1731 1732 , , , 1733 1736 and and CC 1737 1747 J.T.Bruder J.T.Bruder NNP 1747 1748 , , , 1749 1765 J.Virol.70:2260- J.Virol.70:2260- NNP 1766 1770 2268 2268 CD 1770 1771 , , , 1772 1776 1996 1996 CD 1776 1777 ) ) ) 1777 1778 , , , 1779 1784 these these DT 1785 1792 results result NNS 1793 1801 indicate indicate VBP 1802 1803 a a DT 1804 1816 contribution contribution NN 1817 1819 of of IN 1820 1824 GABP GABP NNP 1825 1832 factors factor NNS 1833 1835 to to TO 1836 1839 the the DT 1840 1852 Raf-mediated raf-mediated JJ 1853 1864 enhancement enhancement NN 1865 1867 of of IN 1868 1872 IL-2 il-2 NN 1873 1882 induction induction NN 1883 1889 during during IN 1890 1896 T-cell t-cell NN 1897 1907 activation activation NN 1907 1908 . . .