0 9 Induction Induction NNP 10 12 of of IN 13 18 bcl-2 bcl-2 NN 19 29 expression expression NN 30 32 by by IN 33 47 phosphorylated phosphorylate VBN 48 52 CREB CREB NNP 53 61 proteins protein NNS 62 68 during during IN 69 75 B-cell b-cell NN 76 86 activation activation NN 87 90 and and CC 91 97 rescue rescue NN 98 102 from from IN 103 112 apoptosis apoptosis NN 112 113 . . . 115 125 Engagement engagement NN 126 128 of of IN 129 136 surface surface NN 137 151 immunoglobulin immunoglobulin NN 152 154 on on IN 155 161 mature mature JJ 162 163 B B NNP 164 169 cells cell NNS 170 175 leads lead VBZ 176 178 to to TO 179 185 rescue rescue NN 186 190 from from IN 191 200 apoptosis apoptosis NN 201 204 and and CC 205 207 to to TO 208 221 proliferation proliferation NN 221 222 . . . 223 229 Levels level NNS 230 232 of of IN 233 238 bcl-2 bcl-2 NN 239 243 mRNA mrna NN 244 247 and and CC 248 255 protein protein NN 256 264 increase increase VBP 265 269 with with IN 270 283 cross-linking cross-linking NN 284 286 of of IN 287 294 surface surface NN 295 309 immunoglobulin immunoglobulin NN 309 310 . . . 311 313 We we PRP 314 318 have have VBP 319 326 located locate VBN 327 330 the the DT 331 336 major major JJ 337 345 positive positive JJ 346 356 regulatory regulatory JJ 357 363 region region NN 364 367 for for IN 368 375 control control NN 376 378 of of IN 379 384 bcl-2 bcl-2 NN 385 395 expression expression NN 396 398 in in IN 399 400 B B NNP 401 406 cells cell NNS 407 409 in in IN 410 413 the the DT 414 425 5’-flanking 5'-flanking JJ 426 432 region region NN 432 433 . . . 434 437 The the DT 438 446 positive positive JJ 447 453 region region NN 454 457 can can MD 458 460 be be VB 461 468 divided divide VBN 469 473 into into IN 474 476 an an DT 477 485 upstream upstream JJ 486 489 and and CC 490 491 a a DT 492 502 downstream downstream JJ 503 513 regulatory regulatory JJ 514 520 region region NN 520 521 . . . 522 525 The the DT 526 536 downstream downstream JJ 537 547 regulatory regulatory JJ 548 554 region region NN 555 563 contains contain VBZ 564 565 a a DT 566 572 cyclic cyclic JJ 573 587 AMP-responsive amp-responsive JJ 588 595 element element NN 596 597 ( ( ( 597 600 CRE CRE NNP 600 601 ) ) ) 601 602 . . . 603 605 We we PRP 606 610 show show VBP 611 613 by by IN 614 622 antibody antibody NN 623 633 supershift supershift NN 634 645 experiments experiment NNS 646 649 and and CC 650 652 UV UV NNP 653 666 cross-linking cross-linking NN 667 675 followed follow VBN 676 678 by by IN 679 689 denaturing denature VBG 690 704 polyacrylamide polyacrylamide NN 705 708 gel gel NN 709 724 electrophoresis electrophoresis NN 725 729 that that IN 730 734 both both CC 735 739 CREB CREB NNP 740 743 and and CC 744 747 ATF ATF NNP 748 754 family family NN 755 762 members member NNS 763 767 bind bind VBP 768 770 to to TO 771 775 this this DT 776 782 region region NN 783 785 in in FW 786 791 vitro vitro FW 791 792 . . . 793 802 Mutations mutation NNS 803 805 of of IN 806 809 the the DT 810 813 CRE CRE NNP 814 818 site site NN 819 823 that that WDT 824 830 result result VBP 831 833 in in IN 834 838 loss loss NN 839 841 of of IN 842 846 CREB CREB NNP 847 854 binding binding NN 855 859 also also RB 860 864 lead lead VBP 865 867 to to TO 868 872 loss loss NN 873 875 of of IN 876 886 functional functional JJ 887 895 activity activity NN 896 898 of of IN 899 902 the the DT 903 908 bcl-2 bcl-2 NN 909 917 promoter promoter NN 918 920 in in IN 921 943 transient-transfection transient-transfection NN 944 950 assays assay NNS 950 951 . . . 952 955 The the DT 956 964 presence presence NN 965 967 of of IN 968 970 an an DT 971 977 active active JJ 978 981 CRE cre NN 982 986 site site NN 987 989 in in IN 990 993 the the DT 994 999 bcl-2 bcl-2 NN 1000 1008 promoter promoter NN 1009 1016 implies imply VBZ 1017 1021 that that IN 1022 1025 the the DT 1026 1036 regulation regulation NN 1037 1039 of of IN 1040 1045 bcl-2 bcl-2 NN 1046 1056 expression expression NN 1057 1059 is be VBZ 1060 1066 linked link VBN 1067 1069 to to TO 1070 1071 a a DT 1072 1078 signal signal NN 1079 1091 transduction transduction NN 1092 1099 pathway pathway NN 1100 1102 in in IN 1103 1104 B B NNP 1105 1110 cells cell NNS 1110 1111 . . . 1112 1121 Treatment Treatment NNP 1122 1124 of of IN 1125 1128 the the DT 1129 1135 mature mature JJ 1136 1142 B-cell b-cell NN 1143 1147 line line NN 1148 1154 BAL-17 bal-17 NN 1155 1159 with with IN 1160 1166 either either CC 1167 1186 anti-immunoglobulin anti-immunoglobulin JJ 1187 1188 M M NNP 1189 1191 or or CC 1192 1199 phorbol phorbol NN 1200 1212 12-myristate 12-myristate NN 1213 1223 13-acetate 13-acetate NN 1224 1229 leads lead VBZ 1230 1232 to to TO 1233 1235 an an DT 1236 1244 increase increase NN 1245 1247 in in IN 1248 1253 bcl-2 bcl-2 NN 1254 1264 expression expression NN 1265 1269 that that WDT 1270 1272 is be VBZ 1273 1281 mediated mediate VBN 1282 1284 by by IN 1285 1288 the the DT 1289 1292 CRE CRE NNP 1293 1297 site site NN 1297 1298 . . . 1299 1308 Treatment Treatment NNP 1309 1311 of of IN 1312 1315 the the DT 1316 1320 more more RBR 1321 1329 immature immature JJ 1330 1336 B-cell b-cell NN 1337 1341 line line NN 1341 1342 , , , 1343 1348 Ramos Ramos NNP 1348 1349 , , , 1350 1354 with with IN 1355 1362 phorbol phorbol NN 1363 1369 esters ester NNS 1370 1377 rescues rescue VBZ 1378 1381 the the DT 1382 1387 cells cell NNS 1388 1392 from from IN 1393 1410 calcium-dependent calcium-dependent JJ 1411 1421 apoptosis. apoptosis. NN 1422 1427 bcl-2 bcl-2 NN 1428 1438 expression expression NN 1439 1441 is be VBZ 1442 1451 increased increase VBN 1452 1461 following follow VBG 1462 1469 phorbol phorbol NN 1470 1475 ester ester NN 1476 1485 treatment treatment NN 1485 1486 , , , 1487 1490 and and CC 1491 1494 the the DT 1495 1504 increased increase VBN 1505 1515 expression expression NN 1516 1518 is be VBZ 1519 1528 dependent dependent JJ 1529 1531 on on IN 1532 1535 the the DT 1536 1539 CRE CRE NNP 1540 1544 site site NN 1544 1545 . . . 1546 1551 These these DT 1552 1559 stimuli stimulus NNS 1560 1566 result result VBP 1567 1569 in in IN 1570 1585 phosphorylation phosphorylation NN 1586 1588 of of IN 1589 1593 CREB CREB NNP 1594 1596 at at IN 1597 1603 serine serine NN 1604 1607 133 133 CD 1607 1608 . . . 1609 1612 The the DT 1613 1628 phosphorylation phosphorylation NN 1629 1631 of of IN 1632 1636 CREB CREB NNP 1637 1641 that that WDT 1642 1649 results result VBZ 1650 1652 in in IN 1653 1663 activation activation NN 1664 1666 is be VBZ 1667 1675 mediated mediate VBN 1676 1678 by by IN 1679 1686 protein protein NN 1687 1693 kinase kinase NNP 1694 1695 C C NNP 1696 1702 rather rather RB 1703 1707 than than IN 1708 1710 by by IN 1711 1718 protein protein NN 1719 1725 kinase kinase NNP 1726 1727 A A NNP 1727 1728 . . . 1729 1737 Although although IN 1738 1741 the the DT 1742 1745 CRE CRE NNP 1746 1750 site site NN 1751 1753 is be VBZ 1754 1763 necessary necessary JJ 1763 1764 , , , 1765 1772 optimal optimal JJ 1773 1782 induction induction NN 1783 1785 of of IN 1786 1791 bcl-2 bcl-2 NN 1792 1802 expression expression NN 1803 1811 requires require VBZ 1812 1825 participation participation NN 1826 1828 of of IN 1829 1832 the the DT 1833 1841 upstream upstream JJ 1842 1852 regulatory regulatory JJ 1853 1860 element element NN 1860 1861 , , , 1862 1872 suggesting suggest VBG 1873 1877 that that IN 1878 1893 phosphorylation phosphorylation NN 1894 1896 of of IN 1897 1901 CREB CREB NNP 1902 1908 alters alter VBZ 1909 1912 its its PRP$ 1913 1924 interaction interaction NN 1925 1929 with with IN 1930 1933 the the DT 1934 1942 upstream upstream JJ 1943 1953 regulatory regulatory JJ 1954 1961 element element NN 1961 1962 . . . 1963 1966 The the DT 1967 1970 CRE CRE NNP 1971 1975 site site NN 1976 1978 in in IN 1979 1982 the the DT 1983 1988 bcl-2 bcl-2 NN 1989 1997 promoter promoter NN 1998 2005 appears appear VBZ 2006 2008 to to TO 2009 2013 play play VB 2014 2015 a a DT 2016 2021 major major JJ 2022 2026 role role NN 2027 2029 in in IN 2030 2033 the the DT 2034 2043 induction induction NN 2044 2046 of of IN 2047 2052 bcl-2 bcl-2 NN 2053 2063 expression expression NN 2064 2070 during during IN 2071 2074 the the DT 2075 2085 activation activation NN 2086 2088 of of IN 2089 2095 mature mature JJ 2096 2097 B B NNP 2098 2103 cells cell NNS 2104 2107 and and CC 2108 2114 during during IN 2115 2118 the the DT 2119 2125 rescue rescue NN 2126 2128 of of IN 2129 2137 immature immature JJ 2138 2139 B B NNP 2140 2145 cells cell NNS 2146 2150 from from IN 2151 2160 apoptosis apoptosis NN 2160 2161 . . . 2162 2164 It it PRP 2165 2167 is be VBZ 2168 2176 possible possible JJ 2177 2181 that that IN 2182 2185 the the DT 2186 2189 CRE CRE NNP 2190 2194 site site NN 2195 2197 is be VBZ 2198 2209 responsible responsible JJ 2210 2213 for for IN 2214 2223 induction induction NN 2224 2226 of of IN 2227 2232 bcl-2 bcl-2 NN 2233 2243 expression expression NN 2244 2246 in in IN 2247 2252 other other JJ 2253 2257 cell cell NN 2258 2263 types type NNS 2263 2264 , , , 2265 2277 particularly particularly RB 2278 2283 those those DT 2284 2286 in in IN 2287 2292 which which WDT 2293 2300 protein protein NN 2301 2307 kinase kinase NNP 2308 2309 C C NNP 2310 2312 is be VBZ 2313 2321 involved involve VBN 2321 2322 . . .