{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T23:56:02Z","timestamp":1770508562647,"version":"3.49.0"},"reference-count":53,"publisher":"The Royal Society","issue":"11","license":[{"start":{"date-parts":[[2014,11,1]],"date-time":"2014-11-01T00:00:00Z","timestamp":1414800000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/royalsociety.org\/journals\/ethics-policies\/data-sharing-mining\/"}],"content-domain":{"domain":["royalsocietypublishing.org"],"crossmark-restriction":true},"short-container-title":["Open Biol."],"published-print":{"date-parts":[[2014,11]]},"abstract":"<jats:p>\n            Internal ribosome entry sites (IRESs) in cellular mRNAs direct expression of growth-promoting factors through an alternative translation mechanism that has yet to be fully defined. Lymphoid enhancer factor-1 (LEF-1), a Wnt-mediating transcription factor important for cell survival and metastasis in cancer, is produced via IRES-directed translation, and its mRNA is frequently upregulated in malignancies, including chronic myeloid leukaemia (CML). In this study, we determined that\n            <jats:italic>LEF1<\/jats:italic>\n            expression is regulated by Bcr-Abl, the oncogenic protein that drives haematopoietic cell transformation to CML. We have previously shown that the\n            <jats:italic>LEF1<\/jats:italic>\n            5\u2032 untranslated region recruits a complex of proteins to its IRES, including the translation initiation factor eIF4A. In this report, we use two small molecule inhibitors, PP242 (dual mTOR (mammalian target of rapamycin) kinase inhibitor) and hippuristanol (eIF4A inhibitor), to define IRES regulation via a Bcr-Abl\u2013mTOR\u2013eIF4A axis in CML cell lines and primary patient leukaemias. We found that\n            <jats:italic>LEF1<\/jats:italic>\n            and other IRESs are uniquely sensitive to the activities of Bcr-Abl\/mTOR. Most notably, we discovered that eIF4A, an RNA helicase, elicits potent non-canonical effects on the\n            <jats:italic>LEF1<\/jats:italic>\n            IRES. Hippuristanol inhibition of eIF4A stalls translation of IRES mRNA and triggers dissociation from polyribosomes. We propose that a combination drug strategy which targets mTOR and IRES-driven translation disrupts key factors that contribute to growth and proliferation in CML.\n          <\/jats:p>","DOI":"10.1098\/rsob.140180","type":"journal-article","created":{"date-parts":[[2014,11,13]],"date-time":"2014-11-13T03:55:44Z","timestamp":1415850944000},"page":"140180","update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["A novel Bcr-Abl\u2013mTOR\u2013eIF4A axis regulates IRES-mediated translation of LEF-1"],"prefix":"10.1098","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1995-802X","authenticated-orcid":false,"given":"Becky Pinjou","family":"Tsai","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"Jimenez","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharon","family":"Lim","sequence":"additional","affiliation":[{"name":"Cancer and Stem Cell Biology Signature Research Program, Duke\u2013NUS Graduate Medical School, Singapore"},{"name":"Department of Haematology, Singapore General Hospital, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kerry D.","family":"Fitzgerald","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, School of Medicine, University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles T. H.","family":"Chuah","sequence":"additional","affiliation":[{"name":"Cancer and Stem Cell Biology Signature Research Program, Duke\u2013NUS Graduate Medical School, Singapore"},{"name":"Department of Haematology, Singapore General Hospital, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haley","family":"Axelrod","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luke","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. Tiong","family":"Ong","sequence":"additional","affiliation":[{"name":"Cancer and Stem Cell Biology Signature Research Program, Duke\u2013NUS Graduate Medical School, Singapore"},{"name":"Department of Haematology, Singapore General Hospital, Singapore"},{"name":"Department of Medical Oncology, National Cancer Centre, Singapore"},{"name":"Department of Medicine, Duke University Medical Center, Durham, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bert L.","family":"Semler","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marian L.","family":"Waterman","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"175","published-online":{"date-parts":[[2014,11]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00005-008-0029-y"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03319"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20071875"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01593"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-02-411827"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1186\/1756-8722-3-33"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040258"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e11-06-0483"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1474"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510423103"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0900189106"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00105-06"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.4161\/cc.10.2.14472"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2009.07.004"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms141121705"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-09-3732"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.02.010"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2091"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207618"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10912"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401606"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2672"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209901"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207546"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00477-08"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M110.007385"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M707934200"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1261\/rna.7226105"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002127"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-05-501569"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0501-53"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2012.04.039"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio776"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1017\/S135583820100108X"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013030"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.105"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.944801"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.18.6945-6957.2000"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0909773106"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.1.139"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(02)00096-X"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa055229"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1000038"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/897025"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-0752"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.00542"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-0433"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1002\/med.21260"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.23.10556-10565.2005"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.83"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3083"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00642-6"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-12-399519"}],"container-title":["Open Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rsob.140180","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/doi\/full-xml\/10.1098\/rsob.140180","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rsob.140180","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T00:55:55Z","timestamp":1613609755000},"score":1,"resource":{"primary":{"URL":"https:\/\/royalsocietypublishing.org\/doi\/10.1098\/rsob.140180"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,11]]},"references-count":53,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2014,11]]}},"alternative-id":["10.1098\/rsob.140180"],"URL":"https:\/\/doi.org\/10.1098\/rsob.140180","relation":{},"ISSN":["2046-2441"],"issn-type":[{"value":"2046-2441","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,11]]},"assertion":[{"value":"2014-10-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-10-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-11-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}