0 7 Hypoxia Hypoxia NNP 8 14 causes cause VBZ 15 18 the the DT 19 29 activation activation NN 30 32 of of IN 33 40 nuclear nuclear JJ 41 47 factor factor NN 48 53 kappa kappa NN 54 55 B b NN 56 63 through through IN 64 67 the the DT 68 83 phosphorylation phosphorylation NN 84 86 of of IN 87 88 I i NN 89 94 kappa kappa NN 95 96 B B NNP 97 102 alpha alpha NN 103 105 on on IN 106 114 tyrosine tyrosine NN 115 123 residues residue NNS 123 124 . . . 126 129 The the DT 130 138 response response NN 139 141 of of IN 142 151 mammalian mammalian JJ 152 157 cells cell NNS 158 160 to to TO 161 167 stress stress NN 168 170 is be VBZ 171 181 controlled control VBN 182 184 by by IN 185 200 transcriptional transcriptional JJ 201 211 regulatory regulatory JJ 212 220 proteins protein NNS 221 225 such such JJ 226 228 as as IN 229 236 nuclear nuclear JJ 237 243 factor factor NN 244 249 kappa kappa NN 250 251 B B NNP 252 253 ( ( ( 253 261 NF-kappa NF-kappa NNP 262 263 B B NNP 263 264 ) ) ) 265 267 to to TO 268 274 induce induce VB 275 276 a a DT 277 281 wide wide JJ 282 289 variety variety NN 290 292 of of IN 293 298 early early JJ 299 307 response response NN 308 313 genes gene NNS 313 314 . . . 315 317 In in IN 318 322 this this DT 323 329 report report NN 329 330 , , , 331 333 we we PRP 334 338 show show VBP 339 343 that that IN 344 352 exposure exposure NN 353 355 of of IN 356 361 cells cell NNS 362 364 to to TO 365 372 hypoxia hypoxia NN 373 374 ( ( ( 374 378 0.02 0.02 CD 378 379 % % NN 380 382 O2 o2 NN 382 383 ) ) ) 384 391 results result VBZ 392 394 in in IN 395 396 I i NN 397 402 kappa kappa NN 403 404 B B NNP 405 410 alpha alpha NN 411 422 degradation degradation NN 422 423 , , , 424 433 increased increase VBD 434 442 NF-kappa NF-kappa NNP 443 444 B B NNP 445 448 DNA DNA NNP 449 456 binding binding NN 457 465 activity activity NN 465 466 , , , 467 470 and and CC 471 486 transactivation transactivation NN 487 489 of of IN 490 491 a a DT 492 500 reporter reporter NN 501 505 gene gene NN 506 515 construct construct NN 516 526 containing contain VBG 527 530 two two CD 531 539 NF-kappa NF-kappa NNP 540 541 B B NNP 542 545 DNA DNA NNP 546 553 binding binding NN 554 559 sites site NNS 559 560 . . . 561 573 Pretreatment Pretreatment NNP 574 576 of of IN 577 582 cells cell NNS 583 587 with with IN 588 595 protein protein NN 596 604 tyrosine tyrosine NN 605 611 kinase kinase NNP 612 622 inhibitors inhibitor NNS 623 626 and and CC 627 630 the the DT 631 639 dominant dominant JJ 640 648 negative negative JJ 649 655 allele allele NN 656 658 of of IN 659 666 c-Raf-1 c-raf-1 NN 667 668 ( ( ( 668 671 Raf Raf NNP 672 675 301 301 CD 675 676 ) ) ) 677 686 inhibited inhibit VBD 687 688 I i NN 689 694 kappa kappa NN 695 696 B B NNP 697 702 alpha alpha NN 703 714 degradation degradation NN 714 715 , , , 716 724 NF-kappa NF-kappa NNP 725 726 B B NNP 727 734 binding binding NN 734 735 , , , 736 739 and and CC 740 755 transactivation transactivation NN 756 758 of of IN 759 764 kappa kappa NN 765 766 B B NNP 767 775 reporter reporter NN 776 786 constructs construct NNS 787 789 by by IN 790 797 hypoxia hypoxia NN 797 798 . . . 799 801 To to TO 802 813 demonstrate demonstrate VB 814 815 a a DT 816 822 direct direct JJ 823 827 link link NN 828 835 between between IN 836 843 changes change NNS 844 846 in in IN 847 850 the the DT 851 866 phosphorylation phosphorylation NN 867 874 pattern pattern NN 875 877 of of IN 878 879 I i NN 880 885 kappa kappa NN 886 887 B B NNP 888 893 alpha alpha NN 894 898 with with IN 899 907 NF-kappa NF-kappa NNP 908 909 B B NNP 910 920 activation activation NN 920 921 , , , 922 924 we we PRP 925 943 immunoprecipitated immunoprecipitate VBD 944 945 I i NN 946 951 kappa kappa NN 952 953 B B NNP 954 959 alpha alpha NN 960 965 after after IN 966 973 varying vary VBG 974 979 times time NNS 980 982 of of IN 983 990 hypoxic hypoxic JJ 991 999 exposure exposure NN 1000 1003 and and CC 1004 1009 found find VBD 1010 1014 that that IN 1015 1018 its its PRP$ 1019 1027 tyrosine tyrosine NN 1028 1043 phosphorylation phosphorylation NN 1044 1050 status status NN 1051 1060 increased increase VBD 1061 1067 during during IN 1068 1075 hypoxic hypoxic JJ 1076 1084 exposure exposure NN 1084 1085 . . . 1086 1096 Inhibition Inhibition NNP 1097 1099 of of IN 1100 1103 the the DT 1104 1112 transfer transfer NN 1113 1115 of of IN 1116 1124 tyrosine tyrosine NN 1125 1135 phosphoryl phosphoryl NN 1136 1142 groups group NNS 1143 1147 onto onto IN 1148 1149 I i NN 1150 1155 kappa kappa NN 1156 1157 B B NNP 1158 1163 alpha alpha NN 1164 1173 prevented prevent VBD 1174 1175 I i NN 1176 1181 kappa kappa NN 1182 1183 B B NNP 1184 1189 alpha alpha NN 1190 1201 degradation degradation NN 1202 1205 and and CC 1206 1214 NF-kappa NF-kappa NNP 1215 1216 B B NNP 1217 1224 binding binding NN 1224 1225 . . . 1226 1228 In in IN 1229 1239 comparison comparison NN 1240 1242 to to TO 1243 1248 other other JJ 1249 1259 activators activator NNS 1260 1262 of of IN 1263 1271 NF-kappa NF-kappa NNP 1272 1273 B B NNP 1274 1278 such such JJ 1279 1281 as as IN 1282 1289 phorbol phorbol NN 1290 1299 myristate myristate NN 1300 1307 acetate acetate NN 1308 1310 or or CC 1311 1316 tumor tumor NN 1317 1325 necrosis necrosis NN 1326 1332 factor factor NN 1332 1333 , , , 1334 1336 we we PRP 1337 1340 did do VBD 1341 1344 not not RB 1345 1351 detect detect VB 1352 1359 changes change NNS 1360 1362 in in IN 1363 1366 the the DT 1367 1375 tyrosine tyrosine NN 1376 1391 phosphorylation phosphorylation NN 1392 1398 status status NN 1399 1401 of of IN 1402 1403 I i NN 1404 1409 kappa kappa NN 1410 1411 B B NNP 1412 1417 alpha alpha NN 1418 1427 following follow VBG 1428 1437 treatment treatment NN 1438 1442 with with IN 1443 1449 either either DT 1450 1452 of of IN 1453 1458 these these DT 1459 1465 agents agent NNS 1465 1466 . . . 1467 1472 These these DT 1473 1480 results result NNS 1481 1488 suggest suggest VBP 1489 1493 that that IN 1494 1502 tyrosine tyrosine NN 1503 1518 phosphorylation phosphorylation NN 1519 1521 of of IN 1522 1523 I i NN 1524 1529 kappa kappa NN 1530 1531 B B NNP 1532 1537 alpha alpha NN 1538 1544 during during IN 1545 1552 hypoxia hypoxia NN 1553 1555 is be VBZ 1556 1558 an an DT 1559 1568 important important JJ 1569 1577 proximal proximal JJ 1578 1582 step step NN 1583 1588 which which WDT 1589 1597 precedes precede VBZ 1598 1601 its its PRP$ 1602 1614 dissociation dissociation NN 1615 1618 and and CC 1619 1630 degradation degradation NN 1631 1635 from from IN 1636 1644 NF-kappa NF-kappa NNP 1645 1646 B B NNP 1646 1647 . . .