;PMID: 10700176 ;source_file_1359.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..32] = [t:0..32] ;1)sentence:[e:37..159] = [t:37..159] ;2)section:[e:163..330] = [t:163..330] ;3)section:[e:334..458] = [t:334..458] ;4)sentence:[e:462..535] = [t:462..535] ;5)sentence:[e:536..736] = [t:536..736] ;6)sentence:[e:737..918] = [t:737..918] ;7)sentence:[e:919..1130] = [t:919..1130] ;8)sentence:[e:1131..1300] = [t:1131..1300] ;9)sentence:[e:1301..1434] = [t:1301..1434] ;10)sentence:[e:1435..1774] = [t:1435..1774] ;11)section:[e:1778..1823] = [t:1778..1823] ;section 0 Span:0..32 ;Nat Genet 2000 Mar;24(3):245-50 (SEC (FRAG (VBG:[0..3] Nat) (IN:[4..9] Genet) (CD:[11..15] 2000) (CD:[16..23] Mar;24-LRB-) (CD:[23..24] 3) (-RRB-:[24..25] -RRB-) (CD:[25..29] :245) (HYPH:[29..30] -) (CD:[30..32] 50))) ;sentence 1 Span:37..159 ;AXIN1 mutations in hepatocellular carcinomas, and growth suppression in ;cancer cells by virus-mediated transfer of AXIN1. ;[37..42]:gene-rna:"AXIN1" ;[56..81]:malignancy:"hepatocellular carcinomas" ;[153..158]:gene-rna:"AXIN1" (SENT (NP-HLN (NP (NP (NP (NN:[37..42] AXIN1) (NNS:[43..52] mutations)) (PP (IN:[53..55] in) (NP (JJ:[56..70] hepatocellular) (NNS:[71..81] carcinomas)))) (,:[81..82] ,) (CC:[83..86] and) (NP (NP (NN:[87..93] growth) (NN:[94..105] suppression)) (PP (IN:[106..108] in) (NP (NN:[109..115] cancer) (NNS:[117..122] cells))))) (PP (IN:[123..125] by) (NP (NP (ADJP (NN:[126..131] virus) (HYPH:[131..132] -) (VBN:[132..140] mediated)) (NN:[141..149] transfer)) (PP (IN:[150..152] of) (NP (NN:[153..158] AXIN1))))) (.:[158..159] .))) ;section 2 Span:163..330 ;Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, ;Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, ;Yamaoka Y, Nakamura Y. (SEC (FRAG (NNP:[163..168] Satoh) (NNP:[169..171] S,) (NNP:[172..177] Daigo) (NNP:[178..179] Y) (,:[179..180] ,) (NNP:[181..189] Furukawa) (NNP:[190..191] Y) (VBD:[191..192] ,) (NNP:[193..197] Kato) (NNP:[198..199] T) (,:[199..200] ,) (NNP:[201..205] Miwa) (NNP:[206..207] N) (VBD:[207..208] ,) (NNP:[209..218] Nishiwaki) (NNP:[219..220] T) (VBD:[220..221] ,) (NNP:[222..229] Kawasoe) (NNP:[230..231] T) (,:[231..232] ,) (NNP:[233..241] Ishiguro) (NNP:[243..244] H) (,:[244..245] ,) (NNP:[246..252] Fujita) (VBD:[253..255] M,) (NNP:[256..262] Tokino) (NNP:[263..264] T) (,:[264..265] ,) (NNP:[266..272] Sasaki) (NNP:[273..274] Y) (,:[274..275] ,) (NNP:[276..282] Imaoka) (NNP:[283..285] S,) (NNP:[286..292] Murata) (VBD:[293..295] M,) (NNP:[296..303] Shimano) (NNP:[304..305] T) (,:[305..306] ,) (NNP:[307..314] Yamaoka) (NNP:[315..316] Y) (,:[316..317] ,) (NNP:[319..327] Nakamura) (NNP:[328..330] Y.))) ;section 3 Span:334..458 ;Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical ;Science, The University of Tokyo, Tokyo, Japan. (SEC (FRAG (NN:[334..344] Laboratory) (IN:[345..347] of) (NNP:[348..357] Molecular) (NNP:[358..366] Medicine) (,:[366..367] ,) (NNP:[368..373] Human) (NNP:[374..380] Genome) (NNP:[381..387] Center) (,:[387..388] ,) (NNP:[389..398] Institute) (IN:[399..401] of) (NNP:[402..409] Medical) (NNP:[411..418] Science) (,:[418..419] ,) (DT:[420..423] The) (NNP:[424..434] University) (IN:[435..437] of) (NNP:[438..443] Tokyo) (,:[443..444] ,) (NNP:[445..450] Tokyo) (,:[450..451] ,) (NNP:[452..457] Japan) (.:[457..458] .))) ;sentence 4 Span:462..535 ;The Wnt signaling pathway is essential for development and organogenesis. ;[466..469]:gene-rna:"Wnt" (SENT (S (NP-SBJ (DT:[462..465] The) (NN:[466..469] Wnt) (NN:[470..479] signaling) (NN:[480..487] pathway)) (VP (VBZ:[488..490] is) (ADJP-PRD (JJ:[491..500] essential) (PP (IN:[501..504] for) (NP (NN:[505..516] development) (CC:[517..520] and) (NN:[521..534] organogenesis))))) (.:[534..535] .))) ;sentence 5 Span:536..736 ;Wnt signaling stabilizes beta-catenin, which accumulates in the cytoplasm, ;binds to 1-cell factor (TCF; also known as lymphocyte enhancer-binding ;factor, LEF) and then upregulates downstream genes. ;[536..539]:gene-rna:"Wnt" ;[562..574]:gene-protein:"beta-catenin" ;[637..640]:gene-protein:"TCF" ;[656..690]:gene-protein:"lymphocyte enhancer-binding factor" ;[692..695]:gene-protein:"LEF" (SENT (S (NP-SBJ (NN:[536..539] Wnt) (NN:[541..550] signaling)) (VP (VBZ:[551..561] stabilizes) (NP (NP (NN:[562..574] beta-catenin)) (,:[574..575] ,) (SBAR (WHNP-1 (WDT:[576..581] which)) (S (NP-SBJ-1 (-NONE-:[581..581] *T*)) (VP (VP (VBZ:[582..593] accumulates) (PP-LOC (IN:[594..596] in) (NP (DT:[597..600] the) (NN:[601..610] cytoplasm)))) (,:[610..611] ,) (VP (VBZ:[612..617] binds) (PP (TO:[618..620] to) (NP (NN:[622..628] 1-cell) (NN:[629..635] factor) (PRN (-LRB-:[636..637] -LRB-) (NP (NP (NN:[637..640] TCF)) (::[640..641] ;) (VP (ADVP (RB:[642..646] also)) (VBN:[647..652] known) (NP (-NONE-:[652..652] *)) (PP (IN:[653..655] as) (NP (NP (NN:[656..666] lymphocyte) (NML (NN:[667..675] enhancer) (HYPH:[675..676] -) (VBG:[676..683] binding)) (NN:[684..690] factor)) (,:[690..691] ,) (NP (NN:[692..695] LEF)))))) (-RRB-:[695..696] -RRB-))))) (CONJP (CC:[697..700] and) (RB:[702..706] then)) (VP (VBZ:[707..718] upregulates) (NP (JJ:[719..729] downstream) (NNS:[730..735] genes)))))))) (.:[735..736] .))) ;sentence 6 Span:737..918 ;Mutations in CTNNB1 (encoding beta-catenin) or APC (adenomatous polyposis ;coli) have been reported in human neoplasms including colon cancers and ;hepatocellular carcinomas (HCCs). ;[750..756]:gene-rna:"CTNNB1" ;[767..779]:gene-protein:"beta-catenin" ;[785..788]:gene-rna:"APC" ;[790..816]:gene-rna:"adenomatous polyposis coli" ;[846..855]:malignancy:"neoplasms" ;[867..880]:malignancy:"colon cancers" ;[885..910]:malignancy:"hepatocellular carcinomas" ;[912..916]:malignancy:"HCCs" (SENT (S (NP-SBJ-1 (NP (NNS:[737..746] Mutations)) (PP (IN:[747..749] in) (NP (NP (NN:[750..756] CTNNB1) (PRN (-LRB-:[757..758] -LRB-) (VP (VBG:[758..766] encoding) (NP (NN:[767..779] beta-catenin))) (-RRB-:[779..780] -RRB-))) (CC:[782..784] or) (NP (NP (NN:[785..788] APC)) (NP (-LRB-:[789..790] -LRB-) (JJ:[790..801] adenomatous) (NN:[802..811] polyposis) (NN:[812..816] coli) (-RRB-:[816..817] -RRB-)))))) (VP (VBP:[818..822] have) (VP (VBN:[823..827] been) (VP (VBN:[828..836] reported) (NP-1 (-NONE-:[836..836] *)) (PP (IN:[837..839] in) (NP (NP (JJ:[840..845] human) (NNS:[846..855] neoplasms)) (PP (VBG:[857..866] including) (NP (NP (NN:[867..872] colon) (NNS:[873..880] cancers)) (CC:[881..884] and) (NP (NP (JJ:[885..899] hepatocellular) (NNS:[900..910] carcinomas)) (NP (-LRB-:[911..912] -LRB-) (NNS:[912..916] HCCs) (-RRB-:[916..917] -RRB-)))))))))) (.:[917..918] .))) ;sentence 7 Span:919..1130 ;Because HCC5 tend to show accumulation of beta-catenin more often than ;mutations in CTNNB1, we looked for mutations in AXIN1, encoding a key factor ;for Wnt signaling, in 6 HCC cell lines and 100 primary HCC5. ;[927..931]:malignancy:"HCC5" ;[962..974]:gene-protein:"beta-catenin" ;[1004..1010]:gene-rna:"CTNNB1" ;[1040..1045]:gene-rna:"AXIN1" ;[1073..1076]:gene-rna:"Wnt" ;[1093..1108]:malignancy:"HCC cell lines" ;[1117..1129]:malignancy:"primary HCC5" (SENT (S (SBAR-PRP (IN:[919..926] Because) (S (NP-SBJ (NN:[927..931] HCC5)) (VP (VBP:[932..936] tend) (S (NP-SBJ (-NONE-:[936..936] *)) (VP (TO:[938..940] to) (VP (VB:[941..945] show) (NP (NP (NN:[946..958] accumulation)) (PP (IN:[959..961] of) (NP (NN:[962..974] beta-catenin)))) (ADVP-TMP (ADVP (RBR:[975..979] more) (RB:[980..985] often)) (PP (IN:[986..990] than) (NP (NP (NNS:[991..1000] mutations)) (PP (IN:[1001..1003] in) (NP (NN:[1004..1010] CTNNB1)))))))))))) (,:[1010..1011] ,) (NP-SBJ (PRP:[1012..1014] we)) (VP (VBD:[1016..1022] looked) (PP-CLR (IN:[1023..1026] for) (NP (NNS:[1027..1036] mutations))) (PP-LOC (IN:[1037..1039] in) (NP (NP (NN:[1040..1045] AXIN1)) (,:[1045..1046] ,) (VP (VBG:[1047..1055] encoding) (NP (DT:[1056..1057] a) (JJ:[1058..1061] key) (NN:[1062..1068] factor)) (PP (IN:[1069..1072] for) (NP (NN:[1073..1076] Wnt) (NN:[1077..1086] signaling)))))) (,:[1086..1087] ,) (PP (IN:[1088..1090] in) (NP (NP (CD:[1091..1092] 6) (NN:[1093..1096] HCC) (NN:[1098..1102] cell) (NNS:[1103..1108] lines)) (CC:[1109..1112] and) (NP (CD:[1113..1116] 100) (JJ:[1117..1124] primary) (NN:[1125..1129] HCC5))))) (.:[1129..1130] .))) ;sentence 8 Span:1131..1300 ;Among the 4 cell lines and 87 HCC5 in which we did not detect CTNNB1 ;mutations, we identified AXIN1 mutations in 3 cell lines and 6 mutations in ;5 of the primary HCCs. ;[1161..1165]:malignancy:"HCC5" ;[1194..1200]:gene-rna:"CTNNB1" ;[1226..1231]:gene-rna:"AXIN1" ;[1287..1299]:malignancy:"primary HCCs" (SENT (S (PP (IN:[1131..1136] Among) (NP (NP (NP (DT:[1137..1140] the) (CD:[1141..1142] 4) (NN:[1143..1147] cell) (NNS:[1148..1153] lines)) (CC:[1154..1157] and) (NP (CD:[1158..1160] 87) (NN:[1161..1165] HCC5))) (SBAR (WHPP-1 (IN:[1166..1168] in) (WHNP (WDT:[1169..1174] which))) (S (NP-SBJ (PRP:[1175..1177] we)) (VP (VBD:[1179..1182] did) (RB:[1183..1186] not) (VP (VB:[1187..1193] detect) (NP (NN:[1194..1200] CTNNB1) (NNS:[1201..1210] mutations)) (PP-1 (-NONE-:[1210..1210] *T*)))))))) (,:[1210..1211] ,) (NP-SBJ (PRP:[1212..1214] we)) (VP (VBD:[1215..1225] identified) (NP (NP (NP (NN:[1226..1231] AXIN1) (NNS:[1232..1241] mutations)) (PP (IN:[1242..1244] in) (NP (CD:[1245..1246] 3) (NN:[1247..1251] cell) (NNS:[1252..1257] lines)))) (CC:[1259..1262] and) (NP (NP (CD:[1263..1264] 6) (NNS:[1265..1274] mutations)) (PP (IN:[1275..1277] in) (NP (NP (CD:[1278..1279] 5)) (PP (IN:[1280..1282] of) (NP (DT:[1283..1286] the) (JJ:[1287..1294] primary) (NNS:[1295..1299] HCCs)))))))) (.:[1299..1300] .))) ;sentence 9 Span:1301..1434 ;In cell lines containing mutations in either gene, we observed increased DNA ;binding of TCF associated with beta-catenin in nuclei. ;[1390..1393]:gene-protein:"TCF" ;[1411..1423]:gene-protein:"beta-catenin" (SENT (S (PP (IN:[1301..1303] In) (NP (NP (NN:[1304..1308] cell) (NNS:[1309..1314] lines)) (VP (VBG:[1315..1325] containing) (NP (NNS:[1326..1335] mutations)) (PP (IN:[1336..1338] in) (NP (DT:[1340..1346] either) (NN:[1347..1351] gene)))))) (,:[1351..1352] ,) (NP-SBJ (PRP:[1353..1355] we)) (VP (VBD:[1356..1364] observed) (NP (NP (NP (VBN:[1365..1374] increased) (NN:[1375..1378] DNA) (NN:[1379..1386] binding)) (PP (IN:[1387..1389] of) (NP (NN:[1390..1393] TCF)))) (VP (VBN:[1394..1404] associated) (NP (-NONE-:[1404..1404] *)) (PP-CLR (IN:[1405..1409] with) (NP (NN:[1411..1423] beta-catenin))))) (PP-LOC (IN:[1424..1426] in) (NP (NNS:[1427..1433] nuclei)))) (.:[1433..1434] .))) ;sentence 10 Span:1435..1774 ;Adenovirus mediated gene transfer of wild-type AXINI induced apoptosis in ;hepatocellular and colorectal cancer cells that had accumulated beta-catenin ;as a consequence of either APC, CTNNB1 or AXIN1 mutation, suggesting that ;axin may be an effective therapeutic molecule for suppressing growth of ;hepatocellular and colorectal cancers. ;[1482..1487]:gene-rna:"AXINI" ;[1510..1524]...[1540..1552]:malignancy:"hepatocellular"..."cancer cells" ;[1529..1552]:malignancy:"colorectal cancer cells" ;[1575..1587]:gene-protein:"beta-catenin" ;[1615..1618]:gene-rna:"APC" ;[1620..1626]:gene-rna:"CTNNB1" ;[1630..1635]:gene-rna:"AXIN1" ;[1663..1667]:gene-protein:"axin" ;[1736..1750]...[1766..1773]:malignancy:"hepatocellular"..."cancers" ;[1755..1773]:malignancy:"colorectal cancers" (SENT (S (NP-SBJ (NP (ADJP (NN:[1435..1445] Adenovirus) (VBD:[1446..1454] mediated)) (NN:[1455..1459] gene) (NN:[1460..1468] transfer)) (PP (IN:[1469..1471] of) (NP (NML (JJ:[1472..1476] wild) (HYPH:[1476..1477] -) (NN:[1477..1481] type)) (NN:[1482..1487] AXINI)))) (VP (VBN:[1489..1496] induced) (NP (NN:[1497..1506] apoptosis)) (PP-LOC (IN:[1507..1509] in) (NP (NP (NP (JJ:[1510..1524] hepatocellular) (NML-4 (-NONE-:[1524..1524] *P*))) (CC:[1525..1528] and) (NP (JJ:[1529..1539] colorectal) (NML-4 (NN:[1540..1546] cancer) (NNS:[1547..1552] cells)))) (SBAR (WHNP-3 (WDT:[1553..1557] that)) (S (NP-SBJ-3 (-NONE-:[1557..1557] *T*)) (VP (VBD:[1558..1561] had) (VP (VBN:[1563..1574] accumulated) (NP (NN:[1575..1587] beta-catenin)) (PP (IN:[1588..1590] as) (NP (NP (DT:[1591..1592] a) (NN:[1593..1604] consequence)) (PP (IN:[1605..1607] of) (NP (CC:[1608..1614] either) (NP (NN:[1615..1618] APC) (NML-2 (-NONE-:[1618..1618] *P*))) (,:[1618..1619] ,) (NP (NN:[1620..1626] CTNNB1) (NML-2 (-NONE-:[1626..1626] *P*))) (CC:[1627..1629] or) (NP (NN:[1630..1635] AXIN1) (NML-2 (NN:[1637..1645] mutation))))))))))))) (,:[1645..1646] ,) (S-ADV (NP-SBJ (-NONE-:[1646..1646] *)) (VP (VBG:[1647..1657] suggesting) (SBAR (IN:[1658..1662] that) (S (NP-SBJ (NN:[1663..1667] axin)) (VP (MD:[1668..1671] may) (VP (VB:[1672..1674] be) (NP-PRD (NP (DT:[1675..1677] an) (JJ:[1678..1687] effective) (JJ:[1688..1699] therapeutic) (NN:[1700..1708] molecule)) (PP (IN:[1709..1712] for) (S-NOM (NP-SBJ (-NONE-:[1712..1712] *)) (VP (VBG:[1714..1725] suppressing) (NP (NP (NN:[1726..1732] growth)) (PP (IN:[1733..1735] of) (NP (NP (JJ:[1736..1750] hepatocellular) (NML-1 (-NONE-:[1750..1750] *P*))) (CC:[1751..1754] and) (NP (JJ:[1755..1765] colorectal) (NML-1 (NNS:[1766..1773] cancers))))))))))))))))) (.:[1773..1774] .))) ;section 11 Span:1778..1823 ;PMID: 10700176 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[1778..1782] PMID) (::[1782..1783] :) (CD:[1784..1792] 10700176) (IN:[1793..1794] -LSB-) (NNP:[1794..1800] PubMed) (HYPH:[1801..1802] -) (JJ:[1803..1810] indexed) (IN:[1811..1814] for) (NNP:[1815..1823] MEDLINE-RSB-)))