;PMID: 10192393 ;source_file_1216.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..31] = [t:0..31] ;1)sentence:[e:36..113] = [t:36..113] ;2)section:[e:117..152] = [t:117..152] ;3)section:[e:156..288] = [t:156..288] ;4)sentence:[e:292..355] = [t:292..355] ;5)sentence:[e:356..528] = [t:356..528] ;6)sentence:[e:530..696] = [t:530..696] ;7)sentence:[e:697..964] = [t:697..964] ;8)sentence:[e:965..1118] = [t:965..1118] ;9)sentence:[e:1119..1368] = [t:1119..1368] ;10)sentence:[e:1369..1450] = [t:1369..1450] ;11)sentence:[e:1451..1592] = [t:1451..1592] ;12)sentence:[e:1593..1775] = [t:1593..1775] ;13)sentence:[e:1776..1995] = [t:1776..1995] ;14)section:[e:1999..2044] = [t:1999..2044] ;section 0 Span:0..31 ;Nat Genet 1999 Apr;21(4):410-3 (SEC (FRAG (NNP:[0..3] Nat) (NNP:[4..9] Genet) (CD:[11..15] 1999) (.:[16..23] Apr;21-LRB-) (CD:[23..25] 4-RRB-) (CD:[25..29] :410) (::[29..30] -) (CD:[30..31] 3))) ;sentence 1 Span:36..113 ;A common human skin tumour is caused by activating mutations in ;beta-catenin. ;[51..62]:malignancy:"skin tumour" ;[100..112]:gene-rna:"beta-catenin" (SENT (S-HLN (NP-SBJ-1 (DT:[36..37] A) (JJ:[38..44] common) (JJ:[45..50] human) (NN:[51..55] skin) (NN:[56..62] tumour)) (VP (VBZ:[63..65] is) (VP (VBN:[66..72] caused) (NP-1 (-NONE-:[72..72] *)) (PP (IN:[73..75] by) (NP-LGS (NP (VBG:[76..86] activating) (NNS:[87..96] mutations)) (PP (IN:[97..99] in) (NP (NN:[100..112] beta-catenin))))))) (.:[112..113] .))) ;section 2 Span:117..152 ;Chan EF, Gat U, McNiff JM, Fuchs E. (SEC (FRAG (NNP:[117..121] Chan) (NNP:[122..124] EF) (,:[124..125] ,) (NNP:[126..129] Gat) (NNP:[130..131] U) (,:[131..132] ,) (NNP:[133..139] McNiff) (NNP:[140..142] JM) (,:[142..143] ,) (NNP:[144..149] Fuchs) (NNP:[150..152] E.))) ;section 3 Span:156..288 ;Howard Hughes Medical Institute, Department of Molecular Genetics and Cell ;Biology, The University of Chicago, Illinois 60637, USA. (SEC (FRAG (NNP:[156..162] Howard) (NNP:[163..169] Hughes) (NNP:[170..177] Medical) (NNP:[178..187] Institute) (,:[187..188] ,) (NNP:[189..199] Department) (IN:[200..202] of) (NNP:[203..212] Molecular) (NNP:[213..221] Genetics) (CC:[222..225] and) (NNP:[226..230] Cell) (NNP:[232..239] Biology) (,:[239..240] ,) (DT:[241..244] The) (NNP:[245..255] University) (IN:[256..258] of) (NNP:[259..266] Chicago) (,:[266..267] ,) (NNP:[268..276] Illinois) (VBD:[277..282] 60637) (NNP:[282..283] ,) (NNP:[284..287] USA) (.:[287..288] .))) ;sentence 4 Span:292..355 ;WNT signalling orchestrates a number of developmental programs. ;[292..295]:gene-generic:"WNT" (SENT (S (NP-SBJ (NN:[292..295] WNT) (NN:[296..306] signalling)) (VP (VBZ:[307..319] orchestrates) (NP (NP (DT:[320..321] a) (NN:[322..328] number)) (PP (IN:[329..331] of) (NP (JJ:[332..345] developmental) (NNS:[346..354] programs))))) (.:[354..355] .))) ;sentence 5 Span:356..528 ;In response to this stimulus, cytoplasmic beta-catenin (encoded by CTNNB1) ;is stabilized, enabling downstream transcriptional activation by members of ;the LEF/TCF family. ;[399..411]:gene-protein:"beta-catenin" ;[424..430]:gene-rna:"CTNNB1" ;[513..516]:gene-generic:"LEF" ;[517..520]:gene-generic:"TCF" (SENT (S (PP (IN:[356..358] In) (NP (NP (NN:[359..367] response)) (PP (TO:[368..370] to) (NP (DT:[372..376] this) (NN:[377..385] stimulus))))) (,:[385..386] ,) (NP-SBJ-1 (JJ:[387..398] cytoplasmic) (NN:[399..411] beta-catenin) (PRN (-LRB-:[412..413] -LRB-) (VP (VBN:[413..420] encoded) (NP (-NONE-:[420..420] *)) (PP (IN:[421..423] by) (NP-LGS (NN:[424..430] CTNNB1)))) (-RRB-:[430..431] -RRB-))) (VP (VBZ:[432..434] is) (VP (VBN:[435..445] stabilized) (NP-1 (-NONE-:[445..445] *)) (,:[445..446] ,) (S-ADV (NP-SBJ (-NONE-:[446..446] *)) (VP (VBG:[448..456] enabling) (NP (NP (JJ:[457..467] downstream) (JJ:[468..483] transcriptional) (NN:[484..494] activation)) (PP (IN:[495..497] by) (NP (NP (NNS:[498..505] members)) (PP (IN:[506..508] of) (NP (DT:[509..512] the) (NML (NN:[513..516] LEF) (SYM:[516..517] /) (NN:[517..520] TCF)) (NN:[521..527] family)))))))))) (.:[527..528] .))) ;sentence 6 Span:530..696 ;One of the target genes for beta-catenin/TCF encodes c-MYC, explaining why ;constitutive activation of the WNT pathway can lead to cancer, particularly ;in the colon. ;[558..570]:gene-protein:"beta-catenin" ;[571..574]:gene-protein:"TCF" ;[583..588]:gene-protein:"c-MYC" ;[637..640]:gene-generic:"WNT" ;[661..667]...[682..695]:malignancy:"cancer"..."in the colon" (SENT (S (NP-SBJ (NP (CD:[530..533] One)) (PP (IN:[534..536] of) (NP (NP (DT:[537..540] the) (NN:[541..547] target) (NNS:[548..553] genes)) (PP (IN:[554..557] for) (NP (NN:[558..570] beta-catenin) (SYM:[570..571] /) (NN:[571..574] TCF)))))) (VP (VBZ:[575..582] encodes) (NP (NN:[583..588] c-MYC)) (,:[588..589] ,) (S-ADV (NP-SBJ (-NONE-:[589..589] *)) (VP (VBG:[590..600] explaining) (SBAR-PRP (WRB:[601..604] why) (S (NP-SBJ (NP (JJ:[606..618] constitutive) (NN:[619..629] activation)) (PP (IN:[630..632] of) (NP (DT:[633..636] the) (NN:[637..640] WNT) (NN:[641..648] pathway)))) (VP (MD:[649..652] can) (VP (VB:[653..657] lead) (PP-CLR (TO:[658..660] to) (NP (NP (NN:[661..667] cancer)) (,:[667..668] ,) (PP-LOC (ADVP (RB:[669..681] particularly)) (IN:[682..684] in) (NP (DT:[686..689] the) (NN:[690..695] colon)))))))))))) (.:[695..696] .))) ;sentence 7 Span:697..964 ;Most colon cancers arise from mutations in the gene encoding adenomatous ;polyposis coli (APC), a protein required for ubiquitin-mediated degradation ;of beta-catenin, but a small percentage of colon and some other cancers ;harbour beta-catenin-stabilizing mutations. ;[702..715]:malignancy:"colon cancers" ;[759..785]:gene-protein:"adenomatous polyposis coli" ;[787..790]:gene-protein:"APC" ;[816..825]:gene-protein:"ubiquitin" ;[851..863]:gene-protein:"beta-catenin" ;[891..896]...[913..920]:malignancy:"colon"..."cancers" ;[929..941]:gene-generic:"beta-catenin" (SENT (S (S (NP-SBJ (JJS:[697..701] Most) (NN:[702..707] colon) (NNS:[708..715] cancers)) (VP (VBP:[716..721] arise) (PP-CLR (IN:[722..726] from) (NP (NP (NNS:[727..736] mutations)) (PP-LOC (IN:[737..739] in) (NP (NP (DT:[740..743] the) (NN:[744..748] gene)) (VP (VBG:[749..757] encoding) (NP (NP (NP (JJ:[759..770] adenomatous) (NN:[771..780] polyposis) (NN:[781..785] coli)) (NP (-LRB-:[786..787] -LRB-) (NN:[787..790] APC) (-RRB-:[790..791] -RRB-))) (,:[791..792] ,) (NP (NP (DT:[793..794] a) (NN:[795..802] protein)) (VP (VBN:[803..811] required) (NP (-NONE-:[811..811] *)) (PP (IN:[812..815] for) (NP (NP (ADJP (NN:[816..825] ubiquitin) (HYPH:[825..826] -) (VBN:[826..834] mediated)) (NN:[836..847] degradation)) (PP (IN:[848..850] of) (NP (NN:[851..863] beta-catenin))))))))))))))) (,:[863..864] ,) (CC:[865..868] but) (S (NP-SBJ (NP (DT:[869..870] a) (JJ:[871..876] small) (NN:[877..887] percentage)) (PP (IN:[888..890] of) (NP (NP (NN:[891..896] colon) (NML-1 (-NONE-:[896..896] *P*))) (CC:[897..900] and) (NP (DT:[901..905] some) (JJ:[906..911] other) (NML-1 (NNS:[913..920] cancers)))))) (VP (VBP:[921..928] harbour) (NP (ADJP (NN:[929..941] beta-catenin) (HYPH:[941..942] -) (VBG:[942..953] stabilizing)) (NNS:[954..963] mutations)))) (.:[963..964] .))) ;sentence 8 Span:965..1118 ;Recently, we discovered that transgenic mice expressing an activated ;beta-catenin are predisposed to developing skin tumours resembling ;pilomatricomas. ;[1035..1047]:gene-protein:"beta-catenin" ;[1079..1091]:malignancy:"skin tumours" ;[1103..1117]:malignancy:"pilomatricomas" (SENT (S (ADVP (RB:[965..973] Recently)) (,:[973..974] ,) (NP-SBJ (PRP:[975..977] we)) (VP (VBD:[978..988] discovered) (SBAR (IN:[989..993] that) (S (NP-SBJ-1 (NP (JJ:[995..1005] transgenic) (NNS:[1006..1010] mice)) (VP (VBG:[1011..1021] expressing) (NP (DT:[1022..1024] an) (VBN:[1025..1034] activated) (NN:[1035..1047] beta-catenin)))) (VP (VBP:[1048..1051] are) (VP (VBN:[1052..1063] predisposed) (S (NP-SBJ-1 (-NONE-:[1063..1063] *)) (VP (TO:[1064..1066] to) (VP (VBG:[1068..1078] developing) (NP (NP (NN:[1079..1083] skin) (NNS:[1084..1091] tumours)) (VP (VBG:[1092..1102] resembling) (NP (NNS:[1103..1117] pilomatricomas)))))))))))) (.:[1117..1118] .))) ;sentence 9 Span:1119..1368 ;Given that the skin of these adult mice also exhibits signs of de novo ;hair-follicle morphogenesis, we wondered whether human pilomatricomas might ;originate from hair matrix cells and whether they might possess ;beta-catenin-stabilizing mutations. ;[1247..1261]:malignancy:"pilomatricomas" ;[1333..1345]:gene-generic:"beta-catenin" (SENT (S (PP (VBN:[1119..1124] Given) (SBAR (IN:[1125..1129] that) (S (NP-SBJ (NP (DT:[1130..1133] the) (NN:[1134..1138] skin)) (PP (IN:[1139..1141] of) (NP (DT:[1142..1147] these) (JJ:[1149..1154] adult) (NNS:[1155..1159] mice)))) (ADVP (RB:[1160..1164] also)) (VP (VBZ:[1165..1173] exhibits) (NP (NP (NNS:[1174..1179] signs)) (PP (IN:[1180..1182] of) (NP (ADJP (FW:[1183..1185] de) (FW:[1186..1190] novo)) (NML (NN:[1191..1195] hair) (HYPH:[1195..1196] -) (NN:[1196..1204] follicle)) (NN:[1205..1218] morphogenesis)))))))) (,:[1218..1219] ,) (NP-SBJ (PRP:[1220..1222] we)) (VP (VBD:[1224..1232] wondered) (SBAR (SBAR (IN:[1233..1240] whether) (S (NP-SBJ (JJ:[1241..1246] human) (NNS:[1247..1261] pilomatricomas)) (VP (MD:[1262..1267] might) (VP (VB:[1268..1277] originate) (PP (IN:[1278..1282] from) (NP (NN:[1283..1287] hair) (NN:[1288..1294] matrix) (NNS:[1295..1300] cells))))))) (CC:[1301..1304] and) (SBAR (IN:[1306..1313] whether) (S (NP-SBJ (PRP:[1314..1318] they)) (VP (MD:[1319..1324] might) (VP (VB:[1325..1332] possess) (NP (ADJP (NN:[1333..1345] beta-catenin) (HYPH:[1345..1346] -) (VBG:[1346..1357] stabilizing)) (NNS:[1358..1367] mutations)))))))) (.:[1367..1368] .))) ;sentence 10 Span:1369..1450 ;Here, we explore the cell origin and aetiology of this common human skin ;tumour. ;[1438..1449]:malignancy:"skin tumour" (SENT (S (ADVP (RB:[1369..1373] Here)) (,:[1373..1374] ,) (NP-SBJ (PRP:[1375..1377] we)) (VP (VBP:[1378..1385] explore) (NP (NP (NP (DT:[1387..1390] the) (NN:[1391..1395] cell) (NN:[1396..1402] origin)) (CC:[1403..1406] and) (NP (NN:[1407..1416] aetiology))) (PP (IN:[1417..1419] of) (NP (DT:[1420..1424] this) (JJ:[1425..1431] common) (JJ:[1432..1437] human) (NN:[1438..1442] skin) (NN:[1443..1449] tumour))))) (.:[1449..1450] .))) ;sentence 11 Span:1451..1592 ;We found nuclear LEF-1 in the dividing tumour cells, providing biochemical ;evidence that pilomatricomas are derived from hair matrix cells. ;[1469..1474]:gene-protein:"LEF-1" ;[1491..1503]:malignancy:"tumour cells" ;[1542..1556]:malignancy:"pilomatricomas" (SENT (S (NP-SBJ (PRP:[1451..1453] We)) (VP (VBD:[1454..1459] found) (NP (JJ:[1460..1467] nuclear) (NN:[1469..1474] LEF-1)) (PP-LOC (IN:[1475..1477] in) (NP (DT:[1478..1481] the) (VBG:[1482..1490] dividing) (NN:[1491..1497] tumour) (NNS:[1498..1503] cells))) (,:[1503..1504] ,) (S-ADV (NP-SBJ (-NONE-:[1504..1504] *)) (VP (VBG:[1505..1514] providing) (NP (NP (JJ:[1515..1526] biochemical) (NN:[1527..1535] evidence)) (SBAR (IN:[1536..1540] that) (S (NP-SBJ-1 (NNS:[1542..1556] pilomatricomas)) (VP (VBP:[1557..1560] are) (VP (VBN:[1561..1568] derived) (NP-1 (-NONE-:[1568..1568] *)) (PP (IN:[1569..1573] from) (NP (NN:[1574..1578] hair) (NN:[1579..1585] matrix) (NNS:[1586..1591] cells))))))))))) (.:[1591..1592] .))) ;sentence 12 Span:1593..1775 ;At least 75% of these tumours possess mutations affecting the amino-terminal ;segment, normally involved in phosphorylation-dependent, ubiquitin-mediated ;degradation of the protein. ;[1615..1622]:malignancy:"tumours" ;[1729..1738]:gene-protein:"ubiquitin" (SENT (S (NP-SBJ (NP (QP (IN:[1593..1595] At) (JJS:[1596..1601] least) (CD:[1602..1604] 75)) (NN:[1604..1605] %)) (PP (IN:[1606..1608] of) (NP (DT:[1609..1614] these) (NNS:[1615..1622] tumours)))) (VP (VBP:[1624..1631] possess) (NP (NP (NNS:[1632..1641] mutations)) (VP (VBG:[1642..1651] affecting) (NP (NP (DT:[1652..1655] the) (ADJP (JJ:[1656..1661] amino) (HYPH:[1661..1662] -) (JJ:[1662..1670] terminal)) (NN:[1671..1678] segment)) (,:[1678..1679] ,) (VP (ADVP (RB:[1680..1688] normally)) (VBN:[1689..1697] involved) (NP (-NONE-:[1697..1697] *)) (PP-CLR (IN:[1698..1700] in) (NP (NP (ADJP (NN:[1702..1717] phosphorylation) (HYPH:[1717..1718] -) (JJ:[1718..1727] dependent)) (,:[1727..1728] ,) (ADJP (NN:[1729..1738] ubiquitin) (HYPH:[1738..1739] -) (VBN:[1739..1747] mediated)) (NN:[1748..1759] degradation)) (PP (IN:[1760..1762] of) (NP (DT:[1763..1766] the) (NN:[1767..1774] protein)))))))))) (.:[1774..1775] .))) ;sentence 13 Span:1776..1995 ;This percentage of CTNNB1 mutations is greater than in all other human ;tumours examined thus far, and directly implicates beta-catenin/LEF ;misregulation as the major cause of hair matrix cell tumorigenesis in ;humans. ;[1796..1802]:gene-rna:"CTNNB1" ;[1900..1912]:gene-generic:"beta-catenin" ;[1913..1916]:gene-generic:"LEF" (SENT (S (NP-SBJ (NP (DT:[1776..1780] This) (NN:[1782..1792] percentage)) (PP (IN:[1793..1795] of) (NP (NN:[1796..1802] CTNNB1) (NNS:[1803..1812] mutations)))) (VP (VP (VBZ:[1813..1815] is) (ADJP-PRD (ADJP (JJR:[1816..1823] greater)) (PP (IN:[1824..1828] than) (PP (IN:[1829..1831] in) (NP (NP (DT:[1832..1835] all) (JJ:[1836..1841] other) (JJ:[1842..1847] human) (NNS:[1848..1855] tumours)) (VP (VBN:[1857..1865] examined) (NP (-NONE-:[1865..1865] *)) (ADVP-TMP (RB:[1866..1870] thus) (RB:[1871..1874] far)))))))) (,:[1874..1875] ,) (CC:[1876..1879] and) (VP (ADVP (RB:[1880..1888] directly)) (VBZ:[1889..1899] implicates) (NP (NML (NN:[1900..1912] beta-catenin) (SYM:[1912..1913] /) (NN:[1913..1916] LEF)) (NN:[1917..1930] misregulation)) (PP (IN:[1931..1933] as) (NP (NP (DT:[1934..1937] the) (JJ:[1939..1944] major) (NN:[1945..1950] cause)) (PP (IN:[1951..1953] of) (NP (NN:[1954..1958] hair) (NN:[1959..1965] matrix) (NN:[1966..1970] cell) (NN:[1971..1984] tumorigenesis))))) (PP-LOC (IN:[1985..1987] in) (NP (NNS:[1988..1994] humans))))) (.:[1994..1995] .))) ;section 14 Span:1999..2044 ;PMID: 10192393 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[1999..2003] PMID) (::[2003..2004] :) (CD:[2005..2013] 10192393) (NN:[2014..2015] -LSB-) (NNP:[2015..2021] PubMed) (::[2022..2023] -) (NN:[2024..2031] indexed) (IN:[2032..2035] for) (NNP:[2036..2044] MEDLINE-RSB-)))