;PMID: 9797363 ;source_file_1391.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..40] = [t:0..40] ;1)sentence:[e:45..129] = [t:45..129] ;2)section:[e:133..267] = [t:133..267] ;3)section:[e:271..358] = [t:271..358] ;4)sentence:[e:362..380] = [t:362..380] ;5)sentence:[e:381..437] = [t:381..437] ;6)sentence:[e:439..547] = [t:439..547] ;7)sentence:[e:548..753] = [t:548..753] ;8)sentence:[e:754..826] = [t:754..826] ;9)sentence:[e:828..836] = [t:828..836] ;10)sentence:[e:837..1074] = [t:837..1074] ;11)sentence:[e:1075..1119] = [t:1075..1119] ;12)sentence:[e:1120..1261] = [t:1120..1261] ;13)sentence:[e:1262..1270] = [t:1262..1270] ;14)sentence:[e:1271..1366] = [t:1271..1366] ;15)sentence:[e:1367..1459] = [t:1367..1459] ;16)sentence:[e:1460..1472] = [t:1460..1472] ;17)sentence:[e:1473..1636] = [t:1473..1636] ;18)section:[e:1640..1684] = [t:1640..1684] ;section 0 Span:0..40 ;Gastroenterology 1998 Nov;115(5):1090-5 (SEC (FRAG (IN:[0..16] Gastroenterology) (CD:[18..22] 1998) (CD:[23..31] Nov;115-LRB-) (CD:[31..32] 5) (-RRB-:[32..33] -RRB-) (CD:[33..38] :1090) (HYPH:[38..39] -) (CD:[39..40] 5))) ;sentence 1 Span:45..129 ;A novel gain-of-function mutation of c-kit gene in gastrointestinal stromal ;tumors. ;[82..87]:gene-rna:"c-kit" ;[96..128]:malignancy:"gastrointestinal stromal tumors" (SENT (NP-HLN (NP (DT:[45..46] A) (JJ:[47..52] novel) (NML (NML (NN:[53..57] gain)) (HYPH:[57..58] -) (PP (IN:[58..60] of) (HYPH:[60..61] -) (NP (NN:[61..69] function)))) (NN:[70..78] mutation)) (PP (IN:[79..81] of) (NP (NN:[82..87] c-kit) (NN:[88..92] gene))) (PP (IN:[93..95] in) (NP (JJ:[96..112] gastrointestinal) (JJ:[113..120] stromal) (NNS:[122..128] tumors))) (.:[128..129] .))) ;section 2 Span:133..267 ;Nakahara M, Isozaki K, Hirota S, Miyagawa J, Hase-Sawada N, Taniguchi M, ;Nishida T, Kanayama S, Kitamura Y, Shinomura Y, Matsuzawa Y. (SEC (FRAG (NNP:[133..141] Nakahara) (NNP:[142..144] M,) (NNP:[145..152] Isozaki) (NNP:[153..154] K) (,:[154..155] ,) (NNP:[156..162] Hirota) (NNP:[163..165] S,) (NNP:[166..174] Miyagawa) (NNP:[175..177] J,) (NNP:[178..182] Hase) (HYPH:[182..183] -) (NNP:[183..189] Sawada) (NNP:[190..191] N) (,:[191..192] ,) (NNP:[193..202] Taniguchi) (VBD:[203..205] M,) (NNP:[206..213] Nishida) (NNP:[215..216] T) (,:[216..217] ,) (NNP:[218..226] Kanayama) (NNP:[227..229] S,) (NNP:[230..238] Kitamura) (NNP:[239..240] Y) (,:[240..241] ,) (NNP:[242..251] Shinomura) (NNP:[252..253] Y) (,:[253..254] ,) (NNP:[255..264] Matsuzawa) (NNP:[265..267] Y.))) ;section 3 Span:271..358 ;Second Department of Internal Medicine, Osaka University Medical School, ;Osaka, Japan. (SEC (FRAG (NNP:[271..277] Second) (NNP:[278..288] Department) (DT:[289..291] of) (NNP:[292..300] Internal) (NNP:[301..309] Medicine) (,:[309..310] ,) (NNP:[311..316] Osaka) (NNP:[317..327] University) (NNP:[328..335] Medical) (NNP:[336..342] School) (,:[342..343] ,) (NNP:[344..349] Osaka) (IN:[349..350] ,) (NNP:[352..357] Japan) (.:[357..358] .))) ;sentence 4 Span:362..380 ;BACKGROUND & AIMS: (SENT (NP (NN:[362..372] BACKGROUND) (CC:[373..374] &) (NNS:[375..379] AIMS) (::[379..380] :))) ;sentence 5 Span:381..437 ;The c-kit gene encodes a receptor tyrosine kinase (KIT). ;[385..390]:gene-rna:"c-kit" ;[406..430]:gene-protein:"receptor tyrosine kinase" ;[432..435]:gene-protein:"KIT" (SENT (S (NP-SBJ (DT:[381..384] The) (NN:[385..390] c-kit) (NN:[391..395] gene)) (VP (VBZ:[396..403] encodes) (NP (DT:[404..405] a) (NN:[406..414] receptor) (NML (NML (NN:[415..423] tyrosine) (NN:[424..430] kinase)) (NML (-LRB-:[431..432] -LRB-) (NN:[432..435] KIT) (-RRB-:[435..436] -RRB-))))) (.:[436..437] .))) ;sentence 6 Span:439..547 ;Recently, we found gain-of-function mutations of the c-kit gene in ;gastrointestinal stromal tumors (GISTs). ;[492..497]:gene-rna:"c-kit" ;[507..538]:malignancy:"gastrointestinal stromal tumors" ;[540..545]:malignancy:"GISTs" (SENT (S (ADVP-TMP (RB:[439..447] Recently)) (,:[447..448] ,) (NP-SBJ (PRP:[449..451] we)) (VP (VBD:[452..457] found) (NP (NP (NML (NML (NN:[458..462] gain)) (HYPH:[462..463] -) (PP (IN:[463..465] of) (HYPH:[465..466] -) (NP (NN:[466..474] function)))) (NNS:[475..484] mutations)) (PP (IN:[485..487] of) (NP (NP (DT:[488..491] the) (NN:[492..497] c-kit) (NN:[498..502] gene)) (PP-LOC (IN:[503..505] in) (NP (NP (JJ:[507..523] gastrointestinal) (JJ:[524..531] stromal) (NNS:[532..538] tumors)) (NP (-LRB-:[539..540] -LRB-) (NNS:[540..545] GISTs) (-RRB-:[545..546] -RRB-)))))))) (.:[546..547] .))) ;sentence 7 Span:548..753 ;All mutations were confined within the 11 amino acids (Lys-550 to Val-560) ;in the juxtamembrane domain, but one GIST showed a novel deletion-type ;mutation at codon 579 (Asp) in the juxtamembrane domain. ;[552..561]:variation-event:"mutations" ;[604..622]:variation-location:"Lys-550 to Val-560" ;[661..665]:malignancy:"GIST" ;[682..690]:variation-type:"deletion" ;[696..704]:variation-event:"mutation" ;[708..717]:variation-location:"codon 579" ;[719..722]:variation-state-original:"Asp" (SENT (S (S (NP-SBJ-1 (DT:[548..551] All) (NNS:[552..561] mutations)) (VP (VBD:[562..566] were) (VP (VBN:[567..575] confined) (NP-1 (-NONE-:[575..575] *)) (PP (IN:[576..582] within) (NP (NP (DT:[583..586] the) (CD:[588..590] 11) (JJ:[591..596] amino) (NNS:[597..602] acids) (PRN (-LRB-:[603..604] -LRB-) (NP (NP (NN:[604..611] Lys-550)) (PP (TO:[612..614] to) (NP (NN:[615..622] Val-560)))) (-RRB-:[622..623] -RRB-))) (PP-LOC (IN:[624..626] in) (NP (DT:[627..630] the) (NN:[631..644] juxtamembrane) (NN:[645..651] domain)))))))) (,:[651..652] ,) (CC:[653..656] but) (S (NP-SBJ (CD:[657..660] one) (NN:[661..665] GIST)) (VP (VBD:[667..673] showed) (NP (DT:[674..675] a) (JJ:[676..681] novel) (NML (NN:[682..690] deletion) (HYPH:[690..691] -) (NN:[691..695] type)) (NN:[696..704] mutation)) (PP-LOC (IN:[705..707] at) (NP (NP (NN:[708..713] codon) (CD:[714..717] 579) (PRN (-LRB-:[718..719] -LRB-) (NP (NN:[719..722] Asp)) (-RRB-:[722..723] -RRB-))) (PP-LOC (IN:[724..726] in) (NP (DT:[727..730] the) (NN:[731..744] juxtamembrane) (NN:[746..752] domain))))))) (.:[752..753] .))) ;sentence 8 Span:754..826 ;The aim of this study was to clarify whether the mutation is activating. ;[803..811]:variation-event:"mutation" (SENT (S (NP-SBJ (NP (DT:[754..757] The) (NN:[758..761] aim)) (PP (IN:[762..764] of) (NP (DT:[765..769] this) (NN:[770..775] study)))) (VP (VBD:[776..779] was) (S-NOM-PRD (NP-SBJ (-NONE-:[779..779] *)) (VP (TO:[780..782] to) (VP (VB:[783..790] clarify) (SBAR (IN:[791..798] whether) (S (NP-SBJ (DT:[799..802] the) (NN:[803..811] mutation)) (VP (VBZ:[812..814] is) (ADJP-PRD (VBG:[815..825] activating))))))))) (.:[825..826] .))) ;sentence 9 Span:828..836 ;METHODS: (SENT (NP (NNS:[828..835] METHODS) (::[835..836] :))) ;sentence 10 Span:837..1074 ;Mutant c-kit cDNA was transfected into an interleukin 3 (IL-3)-dependent ;Ba/F3 murine lymphoid cell line, and the magnitude of autophosphorylation of ;the mutant KIT was examined with or without stem cell factor (SCF), a ligand ;of KIT. ;[844..849]:gene-rna:"c-kit" ;[879..892]:gene-protein:"interleukin 3" ;[895..899]:gene-protein:"IL-3" ;[1000..1003]:gene-protein:"KIT" ;[1033..1050]:gene-protein:"stem cell factor" ;[1052..1055]:gene-protein:"SCF" ;[1070..1073]:gene-protein:"KIT" (SENT (S (S (NP-SBJ-2 (JJ:[837..843] Mutant) (NN:[844..849] c-kit) (NN:[850..854] cDNA)) (VP (VBD:[855..858] was) (VP (VBN:[859..870] transfected) (NP-2 (-NONE-:[870..870] *)) (PP (IN:[871..875] into) (NP (DT:[876..878] an) (ADJP (NML (NML (NN:[879..890] interleukin) (CD:[891..892] 3)) (NML (-LRB-:[894..895] -LRB-) (NN:[895..899] IL-3) (-RRB-:[899..900] -RRB-))) (HYPH:[900..901] -) (JJ:[901..910] dependent)) (NML (NN:[911..913] Ba) (SYM:[913..914] /) (NN:[914..916] F3)) (JJ:[917..923] murine) (JJ:[924..932] lymphoid) (NN:[933..937] cell) (NN:[938..942] line)))))) (,:[942..943] ,) (CC:[944..947] and) (S (NP-SBJ-1 (NP (DT:[948..951] the) (NN:[952..961] magnitude)) (PP (IN:[962..964] of) (NP (NP (NN:[966..985] autophosphorylation)) (PP (IN:[986..988] of) (NP (DT:[989..992] the) (JJ:[993..999] mutant) (NN:[1000..1003] KIT)))))) (VP (VBD:[1004..1007] was) (VP (VBN:[1008..1016] examined) (NP-1 (-NONE-:[1016..1016] *)) (PP (IN:[1017..1021] with) (CC:[1022..1024] or) (IN:[1025..1032] without) (NP (NP (NP (NN:[1033..1037] stem) (NN:[1038..1042] cell) (NN:[1044..1050] factor)) (NP (-LRB-:[1051..1052] -LRB-) (NN:[1052..1055] SCF) (-RRB-:[1055..1056] -RRB-))) (,:[1056..1057] ,) (NP (NP (DT:[1058..1059] a) (NN:[1060..1066] ligand)) (PP (IN:[1067..1069] of) (NP (NN:[1070..1073] KIT))))))))) (.:[1073..1074] .))) ;sentence 11 Span:1075..1119 ;An in vitro kinase assay was also performed. ;[1087..1093]:gene-protein:"kinase" (SENT (S (NP-SBJ-1 (DT:[1075..1077] An) (ADJP (FW:[1078..1080] in) (FW:[1081..1086] vitro)) (NN:[1087..1093] kinase) (NN:[1094..1099] assay)) (VP (VBD:[1100..1103] was) (ADVP (RB:[1104..1108] also)) (VP (VBN:[1109..1118] performed) (NP-1 (-NONE-:[1118..1118] *)))) (.:[1118..1119] .))) ;sentence 12 Span:1120..1261 ;The biological behavior of the transfectant was estimated by both an in ;vitro proliferation assay and in vivo transplantation to nude mice. (SENT (S (NP-SBJ-1 (NP (DT:[1120..1123] The) (JJ:[1125..1135] biological) (NN:[1136..1144] behavior)) (PP (IN:[1145..1147] of) (NP (DT:[1148..1151] the) (NN:[1152..1164] transfectant)))) (VP (VBD:[1165..1168] was) (VP (VBN:[1169..1178] estimated) (NP-1 (-NONE-:[1178..1178] *)) (PP (IN:[1179..1181] by) (NP (CC:[1182..1186] both) (NP (DT:[1187..1189] an) (ADJP (FW:[1190..1192] in) (FW:[1193..1198] vitro)) (NN:[1200..1213] proliferation) (NN:[1214..1219] assay)) (CC:[1220..1223] and) (NP (NP (ADJP (FW:[1224..1226] in) (FW:[1227..1231] vivo)) (NN:[1232..1247] transplantation)) (PP (TO:[1248..1250] to) (NP (JJ:[1251..1255] nude) (NNS:[1256..1260] mice)))))))) (.:[1260..1261] .))) ;sentence 13 Span:1262..1270 ;RESULTS: (SENT (NP (NNS:[1262..1269] RESULTS) (::[1269..1270] :))) ;sentence 14 Span:1271..1366 ;The mutant KIT exhibited constitutive phosphorylation and strong kinase ;activity without SCF. ;[1283..1286]:gene-protein:"KIT" ;[1337..1343]:gene-protein:"kinase" ;[1362..1365]:gene-protein:"SCF" (SENT (S (NP-SBJ (DT:[1271..1274] The) (JJ:[1276..1282] mutant) (NN:[1283..1286] KIT)) (VP (VBD:[1287..1296] exhibited) (NP (NP (JJ:[1297..1309] constitutive) (NN:[1310..1325] phosphorylation)) (CC:[1326..1329] and) (NP (JJ:[1330..1336] strong) (NN:[1337..1343] kinase) (NN:[1344..1352] activity))) (PP (IN:[1354..1361] without) (NP (NN:[1362..1365] SCF)))) (.:[1365..1366] .))) ;sentence 15 Span:1367..1459 ;The transfectant grew autonomously without IL-3 and SCF, and it formed ;tumors in nude mice. ;[1410..1414]:gene-protein:"IL-3" ;[1419..1422]:gene-protein:"SCF" ;[1439..1445]:malignancy:"tumors" (SENT (S (S (NP-SBJ (DT:[1367..1370] The) (NN:[1371..1383] transfectant)) (VP (VBD:[1384..1388] grew) (ADVP (RB:[1389..1401] autonomously)) (PP (IN:[1402..1409] without) (NP (NN:[1410..1414] IL-3) (CC:[1415..1418] and) (NN:[1419..1422] SCF))))) (,:[1422..1423] ,) (CC:[1424..1427] and) (S (NP-SBJ (PRP:[1428..1430] it)) (VP (VBD:[1432..1438] formed) (NP (NNS:[1439..1445] tumors)) (PP-LOC (IN:[1446..1448] in) (NP (JJ:[1449..1453] nude) (NNS:[1454..1458] mice))))) (.:[1458..1459] .))) ;sentence 16 Span:1460..1472 ;CONCLUSIONS: (SENT (NP (NNS:[1460..1471] CONCLUSIONS) (::[1471..1472] :))) ;sentence 17 Span:1473..1636 ;Deletion at codon 579 (Asp) in the juxtamembrane domain of the c-kit gene is ;a novel gain-of-function mutation other than the region between Lys-550 and ;Val-560. ;[1473..1481]:variation-type:"Deletion" ;[1485..1494]:variation-location:"codon 579" ;[1496..1499]:variation-state-original:"Asp" ;[1537..1542]:gene-rna:"c-kit" ;[1576..1584]:variation-event:"mutation" ;[1601..1635]:variation-location:"region between Lys-550 and Val-560" (SENT (S (NP-SBJ (NP (NN:[1473..1481] Deletion)) (PP-LOC (IN:[1482..1484] at) (NP (NP (NN:[1485..1490] codon) (CD:[1491..1494] 579) (PRN (-LRB-:[1495..1496] -LRB-) (NP (NN:[1496..1499] Asp)) (-RRB-:[1499..1500] -RRB-))) (PP-LOC (IN:[1501..1503] in) (NP (NP (DT:[1504..1507] the) (NN:[1509..1522] juxtamembrane) (NN:[1523..1529] domain)) (PP (IN:[1530..1532] of) (NP (DT:[1533..1536] the) (NN:[1537..1542] c-kit) (NN:[1543..1547] gene)))))))) (VP (VBZ:[1548..1550] is) (NP-PRD (NP (DT:[1551..1552] a) (JJ:[1553..1558] novel) (NML (NML (NN:[1559..1563] gain)) (HYPH:[1563..1564] -) (PP (IN:[1564..1566] of) (HYPH:[1566..1567] -) (NP (NN:[1567..1575] function)))) (NN:[1576..1584] mutation)) (ADJP (ADJP (JJ:[1586..1591] other)) (PP (IN:[1592..1596] than) (NP (NP (DT:[1597..1600] the) (NN:[1601..1607] region)) (PP-LOC (IN:[1608..1615] between) (NP (NN:[1616..1623] Lys-550) (CC:[1624..1627] and) (NN:[1628..1635] Val-560)))))))) (.:[1635..1636] .))) ;section 18 Span:1640..1684 ;PMID: 9797363 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[1640..1644] PMID) (::[1644..1645] :) (CD:[1646..1653] 9797363) (IN:[1654..1655] -LSB-) (NNP:[1655..1661] PubMed) (HYPH:[1662..1663] -) (JJ:[1664..1671] indexed) (IN:[1672..1675] for) (NNP:[1676..1684] MEDLINE-RSB-)))