0 10 Sequential sequential JJ 11 22 development development NN 23 25 of of IN 26 36 structural structural JJ 37 40 and and CC 41 51 functional functional JJ 52 63 alterations alteration NNS 64 66 in in IN 67 68 T t NN 69 74 cells cell NNS 75 79 from from IN 80 93 tumor-bearing tumor-bearing JJ 94 98 mice mouse NNS 98 99 . . . 101 104 The the DT 105 108 TCR TCR NNP 109 114 alpha alpha NN 115 119 beta beta NN 120 122 or or CC 123 129 -gamma -gamma NN 130 135 delta delta NN 136 142 chains chain NNS 143 147 bind bind VBP 148 151 the the DT 152 159 peptide peptide NN 160 166 ligand ligand NN 166 167 , , , 168 175 whereas whereas IN 176 179 the the DT 180 190 associated associate VBN 191 194 CD3 cd3 NN 195 212 deltaepsilongamma deltaepsilongamma NN 213 216 and and CC 217 220 TCR TCR NNP 221 225 zeta zeta NN 226 234 subunits subunit NNS 235 241 couple couple VBP 242 245 the the DT 246 249 TCR TCR NNP 250 252 to to TO 253 266 intracellular intracellular JJ 267 273 signal signal NN 274 286 transduction transduction NN 287 297 components component NNS 297 298 . . . 299 307 Recently recently RB 307 308 , , , 309 316 several several JJ 317 323 groups group NNS 324 328 have have VBP 329 338 described describe VBN 339 345 marked marked JJ 346 357 alterations alteration NNS 358 360 in in IN 361 367 signal signal NN 368 380 transduction transduction NN 381 389 elements element NNS 390 392 in in IN 393 394 T t NN 395 400 cells cell NNS 401 405 from from IN 406 412 cancer cancer NN 413 421 patients patient NNS 422 424 or or CC 425 427 in in IN 428 432 mice mouse NNS 433 440 bearing bear VBG 441 446 tumor tumor NN 447 450 for for IN 451 452 a a DT 453 456 few few JJ 457 462 weeks week NNS 463 464 ( ( ( 464 467 >26 >26 CD 468 472 days day NNS 472 473 ) ) ) 473 474 . . . 475 478 The the DT 479 487 sequence sequence NN 488 490 in in IN 491 496 which which WDT 497 502 these these DT 503 514 alterations alteration NNS 515 522 develop develop VBP 523 525 is be VBZ 526 533 unknown unknown JJ 533 534 . . . 535 538 The the DT 539 542 aim aim NN 543 545 of of IN 546 550 this this DT 551 556 study study NN 557 560 was be VBD 561 563 to to TO 564 571 explore explore VB 572 575 the the DT 576 584 kinetics kinetic NNS 585 587 of of IN 588 591 the the DT 592 603 development development NN 604 606 of of IN 607 618 alterations alteration NNS 619 621 in in IN 622 628 signal signal NN 629 641 transduction transduction NN 642 651 molecules molecule NNS 652 653 ( ( ( 653 656 TCR TCR NNP 657 661 zeta zeta NN 662 667 chain chain NN 667 668 , , , 669 671 NF NF NNP 672 678 kappaB kappaB NNP 679 685 family family NN 686 694 proteins protein NNS 694 695 , , , 696 699 and and CC 700 708 tyrosine tyrosine NN 709 715 kinase kinase NNP 716 725 p56(lck)) p56(lck)) NN 726 728 in in IN 729 733 mice mouse NNS 734 741 bearing bear VBG 742 746 MC38 mc38 NN 747 752 colon colon NN 753 767 adenocarcinoma adenocarcinoma NN 767 768 . . . 769 772 The the DT 773 780 results result NNS 781 792 demonstrate demonstrate VBP 793 797 that that IN 798 809 alterations alteration NNS 810 812 in in IN 813 815 NF NF NNP 816 822 kappaB kappab NN 823 829 family family NN 830 838 proteins protein NNS 838 839 , , , 840 852 specifically specifically RB 853 856 the the DT 857 864 failure failure NN 865 867 of of IN 868 871 p65 p65 NN 872 885 translocation translocation NN 886 888 to to TO 889 892 the the DT 893 900 nucleus nucleus NN 900 901 , , , 902 907 occur occur VBP 908 915 earlier earlier RBR 916 919 and and CC 920 924 more more RBR 925 935 frequently frequently RB 936 940 than than IN 941 944 the the DT 945 953 decrease decrease NN 954 956 in in IN 957 967 zeta-chain zeta-chain NN 967 968 . . . 969 974 These these DT 975 982 defects defect NNS 983 986 are be VBP 987 997 paralleled parallel VBN 998 1000 by by IN 1001 1003 an an DT 1004 1012 impaired impaired JJ 1013 1020 ability ability NN 1021 1023 to to TO 1024 1031 produce produce VB 1032 1035 Th1 th1 NN 1036 1045 cytokines cytokine NNS 1046 1047 ( ( ( 1047 1051 IL-2 IL-2 NNP 1052 1055 and and CC 1056 1065 IFN-gamma IFN-gamma NNP 1065 1066 ) ) ) 1066 1067 . . . 1068 1073 These these DT 1074 1081 initial initial JJ 1082 1089 changes change NNS 1090 1093 are be VBP 1094 1102 followed follow VBN 1103 1105 by by IN 1106 1109 the the DT 1110 1118 eventual eventual JJ 1119 1123 loss loss NN 1124 1126 of of IN 1127 1130 TCR TCR NNP 1131 1135 zeta zeta NN 1136 1141 chain chain NN 1142 1145 and and CC 1146 1154 p56(lck) p56(lck) NN 1155 1158 and and CC 1159 1160 a a DT 1161 1167 marked marked JJ 1168 1176 decrease decrease NN 1177 1179 in in IN 1180 1189 cytotoxic cytotoxic JJ 1190 1198 function function NN 1198 1199 . . . 1200 1202 An an DT 1203 1212 increased increase VBN 1213 1217 rate rate NN 1218 1220 of of IN 1221 1230 lysosomal lysosomal JJ 1231 1242 degradation degradation NN 1243 1245 is be VBZ 1246 1249 one one CD 1250 1252 of of IN 1253 1256 the the DT 1257 1267 mechanisms mechanism NNS 1268 1279 responsible responsible JJ 1280 1283 for for IN 1284 1287 the the DT 1288 1292 loss loss NN 1293 1295 of of IN 1296 1306 zeta-chain zeta-chain NN 1306 1307 . . .