;PMID: 10766161 ;source_file_1211.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..35] = [t:0..35] ;1)sentence:[e:40..130] = [t:40..130] ;2)section:[e:134..173] = [t:134..173] ;3)section:[e:177..291] = [t:177..291] ;4)sentence:[e:295..436] = [t:295..436] ;5)sentence:[e:437..547] = [t:437..547] ;6)sentence:[e:548..809] = [t:548..809] ;7)sentence:[e:810..1003] = [t:810..1003] ;8)sentence:[e:1005..1080] = [t:1005..1080] ;9)sentence:[e:1081..1258] = [t:1081..1258] ;10)sentence:[e:1259..1373] = [t:1259..1373] ;11)sentence:[e:1374..1607] = [t:1374..1607] ;12)sentence:[e:1608..1784] = [t:1608..1784] ;13)section:[e:1788..1833] = [t:1788..1833] ;section 0 Span:0..35 ;Cancer Res 2000 Apr 1;60(7):1800-4 (SEC (FRAG (NN:[0..6] Cancer) (NNP:[7..10] Res) (CD:[12..16] 2000) (.:[17..20] Apr) (CD:[21..26] 1;60-LRB-) (CD:[26..28] 7-RRB-) (CD:[28..33] :1800) (::[33..34] -) (CD:[34..35] 4))) ;sentence 1 Span:40..130 ;Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma ; cell lines. ;[64..68]:gene-rna:"NRAS" ;[73..77]:gene-rna:"PTEN" ;[78..83]:gene-rna:"MMAC1" ;[99..129]:malignancy:"cutaneous melanoma cell lines" (SENT (NP-HLN (NP (JJ:[40..48] Relative) (NN:[49..60] reciprocity)) (PP (IN:[61..63] of) (NP (NP (NML (NML (NN:[64..68] NRAS)) (CC:[69..72] and) (NML (NN:[73..77] PTEN) (SYM:[77..78] /) (NN:[78..83] MMAC1))) (NNS:[84..95] alterations)) (PP-LOC (IN:[96..98] in) (NP (NML (JJ:[99..108] cutaneous) (NN:[109..117] melanoma)) (NN:[119..123] cell) (NNS:[124..129] lines))))) (.:[129..130] .))) ;section 2 Span:134..173 ;Tsao H, Zhang X, Fowlkes K, Haluska FG. (SEC (FRAG (NNP:[134..138] Tsao) (NNP:[139..140] H) (,:[140..141] ,) (NNP:[142..147] Zhang) (NNP:[148..149] X) (,:[149..150] ,) (NNP:[151..158] Fowlkes) (NNP:[159..160] K) (,:[160..161] ,) (NNP:[162..169] Haluska) (NNP:[170..173] FG.))) ;section 3 Span:177..291 ;Department of Dermatology, Massachusetts General Hospital and ;Dana-Farber/Partners CancerCare, Boston 02114, USA. (SEC (FRAG (NNP:[177..187] Department) (IN:[188..190] of) (NNP:[191..202] Dermatology) (,:[202..203] ,) (NNP:[204..217] Massachusetts) (NNP:[218..225] General) (NNP:[226..234] Hospital) (CC:[235..238] and) (NNP:[240..244] Dana) (::[244..245] -) (NNP:[245..251] Farber) (NNP:[251..252] /) (NNP:[252..260] Partners) (NNP:[261..271] CancerCare) (,:[271..272] ,) (NNP:[273..279] Boston) (VBD:[280..285] 02114) (NNP:[285..286] ,) (NNP:[287..290] USA) (.:[290..291] .))) ;sentence 4 Span:295..436 ;Both inactivation of the tumor suppressor gene, PTEN/MMAC1, and oncogenic ;activation of RAS have been described in human cutaneous melanoma. ;[343..347]:gene-rna:"PTEN" ;[348..353]:gene-rna:"MMAC1" ;[384..387]:gene-rna:"RAS" ;[417..435]:malignancy:"cutaneous melanoma" (SENT (S (NP-SBJ-1 (CC:[295..299] Both) (NP (NP (NN:[300..312] inactivation)) (PP (IN:[313..315] of) (NP (NP (DT:[316..319] the) (NML (NN:[320..325] tumor) (NN:[326..336] suppressor)) (NN:[337..341] gene)) (,:[341..342] ,) (NP (NN:[343..347] PTEN) (SYM:[347..348] /) (NN:[348..353] MMAC1))))) (,:[353..354] ,) (CC:[355..358] and) (NP (NP (JJ:[359..368] oncogenic) (NN:[370..380] activation)) (PP (IN:[381..383] of) (NP (NN:[384..387] RAS))))) (VP (VBP:[388..392] have) (VP (VBN:[393..397] been) (VP (VBN:[398..407] described) (NP-1 (-NONE-:[407..407] *)) (PP (IN:[408..410] in) (NP (JJ:[411..416] human) (JJ:[417..426] cutaneous) (NN:[427..435] melanoma)))))) (.:[435..436] .))) ;sentence 5 Span:437..547 ;In mice, activation of a RAS-containing pathway is a necessary step in the ;pathogenesis of murine melanomas. ;[463..466]:gene-rna:"RAS" ;[537..546]:malignancy:"melanomas" (SENT (S (PP-LOC (IN:[437..439] In) (NP (NNS:[440..444] mice))) (,:[444..445] ,) (NP-SBJ (NP (NN:[447..457] activation)) (PP (IN:[458..460] of) (NP (DT:[461..462] a) (ADJP (NN:[463..466] RAS) (HYPH:[466..467] -) (VBG:[467..477] containing)) (NN:[478..485] pathway)))) (VP (VBZ:[486..488] is) (NP-PRD (NP (DT:[489..490] a) (JJ:[491..500] necessary) (NN:[501..505] step)) (PP (IN:[506..508] in) (NP (NP (DT:[509..512] the) (NN:[513..525] pathogenesis)) (PP (IN:[527..529] of) (NP (JJ:[530..536] murine) (NNS:[537..546] melanomas))))))) (.:[546..547] .))) ;sentence 6 Span:548..809 ;Because PTEN negatively regulates on the downstream effects of ;phosphatidylinositol-3-kinase (PI3-K), we hypothesized that the loss of ;PTEN/MMAC1 and the activation of RAS may be largely equivalent because RAS is ;a known positive upstream regulator of PI3-K. ;[556..560]:gene-rna:"PTEN" ;[612..641]:gene-protein:"phosphatidylinositol-3-kinase" ;[643..648]:gene-protein:"PI3-K" ;[676..680]:variation-type:"loss" ;[685..689]:gene-rna:"PTEN" ;[690..695]:gene-rna:"MMAC1" ;[718..721]:gene-rna:"RAS" ;[756..759]:gene-rna:"RAS" ;[803..808]:gene-protein:"PI3-K" (SENT (S (SBAR-ADV (IN:[548..555] Because) (S (NP-SBJ (NN:[556..560] PTEN)) (ADVP (RB:[561..571] negatively)) (VP (VBZ:[572..581] regulates) (PP (IN:[582..584] on) (NP (NP (DT:[585..588] the) (JJ:[589..599] downstream) (NNS:[600..607] effects)) (PP (IN:[609..611] of) (NP (NP (NN:[612..641] phosphatidylinositol-3-kinase)) (NP (-LRB-:[642..643] -LRB-) (NN:[643..648] PI3-K) (-RRB-:[648..649] -RRB-))))))))) (,:[649..650] ,) (NP-SBJ (PRP:[651..653] we)) (VP (VBD:[654..666] hypothesized) (SBAR (IN:[667..671] that) (S (NP-SBJ (NP (NP (DT:[672..675] the) (NN:[676..680] loss)) (PP (IN:[681..683] of) (NP (NN:[685..689] PTEN) (SYM:[689..690] /) (NN:[690..695] MMAC1)))) (CC:[696..699] and) (NP (NP (DT:[700..703] the) (NN:[704..714] activation)) (PP (IN:[715..717] of) (NP (NN:[718..721] RAS))))) (VP (MD:[722..725] may) (VP (VB:[726..728] be) (ADJP-PRD (RB:[729..736] largely) (JJ:[737..747] equivalent)) (SBAR-ADV (IN:[748..755] because) (S (NP-SBJ (NN:[756..759] RAS)) (VP (VBZ:[760..762] is) (NP-PRD (NP (DT:[763..764] a) (VBN:[766..771] known) (JJ:[772..780] positive) (JJ:[781..789] upstream) (NN:[790..799] regulator)) (PP (IN:[800..802] of) (NP (NN:[803..808] PI3-K)))))))))))) (.:[808..809] .))) ;sentence 7 Span:810..1003 ;We expanded our previous survey of PTEN/MMAC1 mutations and analyzed the RAS ;status of 53 cutaneous melanoma cell lines, 18 glioma cell lines, and 17 ;uncultured cutaneous melanoma metastasis. ;[846..850]:gene-rna:"PTEN" ;[851..856]:gene-rna:"MMAC1" ;[884..887]:gene-rna:"RAS" ;[901..931]:malignancy:"cutaneous melanoma cell lines" ;[936..953]:malignancy:"glioma cell lines" ;[973..1002]:malignancy:"cutaneous melanoma metastasis" (SENT (S (NP-SBJ (PRP:[810..812] We)) (VP (VP (VBD:[813..821] expanded) (NP (NP (PRP$:[822..825] our) (JJ:[826..834] previous) (NN:[835..841] survey)) (PP (IN:[842..844] of) (NP (NML (NN:[846..850] PTEN) (SYM:[850..851] /) (NN:[851..856] MMAC1)) (NNS:[857..866] mutations))))) (CC:[867..870] and) (VP (VBD:[871..879] analyzed) (NP (NP (DT:[880..883] the) (NN:[884..887] RAS) (NN:[888..894] status)) (PP (IN:[895..897] of) (NP (NP (CD:[898..900] 53) (NML (JJ:[901..910] cutaneous) (NN:[911..919] melanoma)) (NN:[920..924] cell) (NNS:[926..931] lines)) (,:[931..932] ,) (NP (CD:[933..935] 18) (NN:[936..942] glioma) (NN:[943..947] cell) (NNS:[948..953] lines)) (,:[953..954] ,) (CC:[955..958] and) (NP (CD:[959..961] 17) (JJ:[962..972] uncultured) (NML (JJ:[973..982] cutaneous) (NN:[983..991] melanoma)) (NN:[992..1002] metastasis))))))) (.:[1002..1003] .))) ;sentence 8 Span:1005..1080 ;Overall, 51% of the cell lines had alterations in either PTEN/MMAC1 or RAS. ;[1025..1035]:malignancy:"cell lines" ;[1062..1066]:gene-rna:"PTEN" ;[1067..1072]:gene-rna:"MMAC1" ;[1076..1079]:gene-rna:"RAS" (SENT (S (ADVP (RB:[1005..1012] Overall)) (,:[1012..1013] ,) (NP-SBJ (NP (CD:[1014..1016] 51) (NN:[1016..1017] %)) (PP (IN:[1018..1020] of) (NP (DT:[1021..1024] the) (NN:[1025..1029] cell) (NNS:[1030..1035] lines)))) (VP (VBD:[1036..1039] had) (NP (NP (NNS:[1040..1051] alterations)) (PP-LOC (IN:[1052..1054] in) (NP (CC:[1055..1061] either) (NP (NN:[1062..1066] PTEN) (SYM:[1066..1067] /) (NN:[1067..1072] MMAC1)) (CC:[1073..1075] or) (NP (NN:[1076..1079] RAS)))))) (.:[1079..1080] .))) ;sentence 9 Span:1081..1258 ;We found 16 cell lines (30%) with alterations in PTEN/MMAC1 and 11 cell ;lines (21%) with activating NRAS mutations; only 1 cell line had concurrent ;alterations in both genes. ;[1094..1104]:malignancy:"cell lines" ;[1131..1135]:gene-rna:"PTEN" ;[1136..1141]:gene-rna:"MMAC1" ;[1149..1159]:malignancy:"cell lines" ;[1183..1187]:gene-rna:"NRAS" ;[1206..1215]:malignancy:"cell line" ;[1252..1257]:gene-rna:"genes" (SENT (S (S (NP-SBJ (PRP:[1081..1083] We)) (VP (VBD:[1085..1090] found) (NP (NP (NP (CD:[1091..1093] 16) (NN:[1094..1098] cell) (NNS:[1099..1104] lines) (PRN (-LRB-:[1105..1106] -LRB-) (NP (CD:[1106..1108] 30) (NN:[1108..1109] %)) (-RRB-:[1109..1110] -RRB-))) (PP (IN:[1111..1115] with) (NP (NP (NNS:[1116..1127] alterations)) (PP (IN:[1128..1130] in) (NP (NN:[1131..1135] PTEN) (SYM:[1135..1136] /) (NN:[1136..1141] MMAC1)))))) (CC:[1142..1145] and) (NP (NP (CD:[1146..1148] 11) (NN:[1149..1153] cell) (NNS:[1154..1159] lines) (PRN (-LRB-:[1160..1161] -LRB-) (NP (CD:[1161..1163] 21) (NN:[1163..1164] %)) (-RRB-:[1164..1165] -RRB-))) (PP (IN:[1167..1171] with) (NP (VBG:[1172..1182] activating) (NN:[1183..1187] NRAS) (NNS:[1188..1197] mutations))))))) (::[1197..1198] ;) (S (NP-SBJ (RB:[1199..1203] only) (CD:[1204..1205] 1) (NN:[1206..1210] cell) (NN:[1211..1215] line)) (VP (VBD:[1216..1219] had) (NP (NP (JJ:[1220..1230] concurrent) (NNS:[1231..1242] alterations)) (PP-LOC (IN:[1243..1245] in) (NP (DT:[1247..1251] both) (NNS:[1252..1257] genes)))))) (.:[1257..1258] .))) ;sentence 10 Span:1259..1373 ;Moreover, glioma cell lines with a high frequency of PTEN/MMAC1 inactivation ;had no identifiable RAS alterations. ;[1269..1286]:malignancy:"glioma cell lines" ;[1312..1316]:gene-rna:"PTEN" ;[1317..1322]:gene-rna:"MMAC1" ;[1357..1360]:gene-rna:"RAS" (SENT (S (ADVP (RB:[1259..1267] Moreover)) (,:[1267..1268] ,) (NP-SBJ (NP (NN:[1269..1275] glioma) (NN:[1276..1280] cell) (NNS:[1281..1286] lines)) (PP (IN:[1287..1291] with) (NP (NP (DT:[1292..1293] a) (JJ:[1294..1298] high) (NN:[1299..1308] frequency)) (PP (IN:[1309..1311] of) (NP (NML (NN:[1312..1316] PTEN) (SYM:[1316..1317] /) (NN:[1317..1322] MMAC1)) (NN:[1324..1336] inactivation)))))) (VP (VBD:[1337..1340] had) (NP (DT:[1341..1343] no) (JJ:[1344..1356] identifiable) (NN:[1357..1360] RAS) (NNS:[1361..1372] alterations))) (.:[1372..1373] .))) ;sentence 11 Span:1374..1607 ;Ectopic expression of PTEN in several cutaneous melanoma cell lines ;suppressed colony formation irrespective of PTEN/MMAC1 status; furthermore, ;PTEN expression in cell lines carrying activated RAS also suppressed colony ;formation. ;[1396..1400]:gene-rna:"PTEN" ;[1413..1442]:malignancy:"cutaneous melanoma cell lines" ;[1488..1492]:gene-rna:"PTEN" ;[1493..1498]:gene-rna:"MMAC1" ;[1520..1524]:gene-rna:"PTEN" ;[1539..1549]:malignancy:"cell lines" ;[1570..1573]:gene-rna:"RAS" (SENT (S (S (NP-SBJ (NP (JJ:[1374..1381] Ectopic) (NN:[1382..1392] expression)) (PP (IN:[1393..1395] of) (NP (NN:[1396..1400] PTEN))) (PP-LOC (IN:[1401..1403] in) (NP (JJ:[1405..1412] several) (NML (JJ:[1413..1422] cutaneous) (NN:[1423..1431] melanoma)) (NN:[1432..1436] cell) (NNS:[1437..1442] lines)))) (VP (VBD:[1443..1453] suppressed) (NP (NN:[1454..1460] colony) (NN:[1461..1470] formation)) (S-ADV (NP-SBJ (-NONE-:[1470..1470] *)) (ADJP-PRD (JJ:[1471..1483] irrespective) (PP (IN:[1485..1487] of) (NP (NML (NN:[1488..1492] PTEN) (SYM:[1492..1493] /) (NN:[1493..1498] MMAC1)) (NN:[1499..1505] status))))))) (::[1505..1506] ;) (S (ADVP (RB:[1507..1518] furthermore)) (,:[1518..1519] ,) (NP-SBJ (NP (NN:[1520..1524] PTEN) (NN:[1525..1535] expression)) (PP-LOC (IN:[1536..1538] in) (NP (NP (NN:[1539..1543] cell) (NNS:[1544..1549] lines)) (VP (VBG:[1550..1558] carrying) (NP (VBN:[1560..1569] activated) (NN:[1570..1573] RAS)))))) (ADVP (RB:[1574..1578] also)) (VP (VBD:[1579..1589] suppressed) (NP (NN:[1590..1596] colony) (NN:[1597..1606] formation)))) (.:[1606..1607] .))) ;sentence 12 Span:1608..1784 ;The relative reciprocity of PTEN/MMAC1 abrogation and NRAS activation ;suggests that the two genetic changes, in a subset of cutaneous melanomas, ;are functionally overlapping. ;[1637..1641]:gene-rna:"PTEN" ;[1642..1647]:gene-rna:"MMAC1" ;[1663..1667]:gene-rna:"NRAS" ;[1734..1753]:malignancy:"cutaneous melanomas" (SENT (S (NP-SBJ (NP (DT:[1608..1611] The) (JJ:[1612..1620] relative) (NN:[1621..1632] reciprocity)) (PP (IN:[1633..1635] of) (NP (NP (NML (NN:[1637..1641] PTEN) (SYM:[1641..1642] /) (NN:[1642..1647] MMAC1)) (NN:[1648..1658] abrogation)) (CC:[1659..1662] and) (NP (NN:[1663..1667] NRAS) (NN:[1668..1678] activation))))) (VP (VBZ:[1679..1687] suggests) (SBAR (IN:[1688..1692] that) (S (NP-SBJ (NP (DT:[1693..1696] the) (CD:[1697..1700] two) (JJ:[1701..1708] genetic) (NNS:[1709..1716] changes)) (,:[1716..1717] ,) (PP (IN:[1719..1721] in) (NP (NP (DT:[1722..1723] a) (NN:[1724..1730] subset)) (PP (IN:[1731..1733] of) (NP (JJ:[1734..1743] cutaneous) (NNS:[1744..1753] melanomas)))))) (,:[1753..1754] ,) (VP (VBP:[1755..1758] are) (ADJP-PRD (ADVP (RB:[1759..1771] functionally)) (VBG:[1772..1783] overlapping)))))) (.:[1783..1784] .))) ;section 13 Span:1788..1833 ;PMID: 10766161 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[1788..1792] PMID) (::[1792..1793] :) (CD:[1794..1802] 10766161) (NN:[1803..1804] -LSB-) (NNP:[1804..1810] PubMed) (::[1811..1812] -) (NN:[1813..1820] indexed) (IN:[1821..1824] for) (NNP:[1825..1833] MEDLINE-RSB-)))