{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:00:39Z","timestamp":1790791239870,"version":"4.1.0"},"reference-count":55,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,1,10]],"date-time":"2020-01-10T00:00:00Z","timestamp":1578614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG 19973."],"award-info":[{"award-number":["IG 19973."]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CNCCS s.c.a.r.l. (www.cnccs.it)","award":["--"],"award-info":[{"award-number":["--"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Eukaryotic initiation factor 6 (eIF6) is necessary for the nucleolar biogenesis of 60S ribosomes. However, most of eIF6 resides in the cytoplasm, where it acts as an initiation factor. eIF6 is necessary for maximal protein synthesis downstream of growth factor stimulation. eIF6 is an antiassociation factor that binds 60S subunits, in turn preventing premature 40S joining and thus the formation of inactive 80S subunits. It is widely thought that eIF6 antiassociation activity is critical for its function. Here, we exploited and improved our assay for eIF6 binding to ribosomes (iRIA) in order to screen for modulators of eIF6 binding to the 60S. Three compounds, eIFsixty-1 (clofazimine), eIFsixty-4, and eIFsixty-6 were identified and characterized. All three inhibit the binding of eIF6 to the 60S in the micromolar range. eIFsixty-4 robustly inhibits cell growth, whereas eIFsixty-1 and eIFsixty-6 might have dose- and cell-specific effects. Puromycin labeling shows that eIF6ixty-4 is a strong global translational inhibitor, whereas the other two are mild modulators. Polysome profiling and RT-qPCR show that all three inhibitors reduce the specific translation of well-known eIF6 targets. In contrast, none of them affect the nucleolar localization of eIF6. These data provide proof of principle that the generation of eIF6 translational modulators is feasible.<\/jats:p>","DOI":"10.3390\/cells9010172","type":"journal-article","created":{"date-parts":[[2020,1,10]],"date-time":"2020-01-10T10:20:29Z","timestamp":1578651629000},"page":"172","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Discovery and Preliminary Characterization of Translational Modulators that Impair the Binding of eIF6 to 60S Ribosomal Subunits"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4214-1904","authenticated-orcid":false,"given":"Elisa","family":"Pesce","sequence":"first","affiliation":[{"name":"National Institute of Molecular Genetics, \u201cFondazione Romeo ed Enrica Invernizzi\u201d, INGM, Via Francesco Sforza 35, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annarita","family":"Miluzio","sequence":"additional","affiliation":[{"name":"National Institute of Molecular Genetics, \u201cFondazione Romeo ed Enrica Invernizzi\u201d, INGM, Via Francesco Sforza 35, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Turcano","sequence":"additional","affiliation":[{"name":"Department of Translational and Discovery Research, IRBM S.p.A., Via Pontina km 30, 600, 00071 Pomezia (Roma), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8350-484X","authenticated-orcid":false,"given":"Claudia","family":"Minici","sequence":"additional","affiliation":[{"name":"Biocrystallography Unit, Dept. of Immunology, Transplantation and Infectious Diseases, IRCCS Scientific Institute San Raffaele, Via Olgettina 58, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delia","family":"Cirino","sequence":"additional","affiliation":[{"name":"National Institute of Molecular Genetics, \u201cFondazione Romeo ed Enrica Invernizzi\u201d, INGM, Via Francesco Sforza 35, 20122 Milan, Italy"},{"name":"DBS, University of Milan, Via Celoria 26, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piera","family":"Calamita","sequence":"additional","affiliation":[{"name":"National Institute of Molecular Genetics, \u201cFondazione Romeo ed Enrica Invernizzi\u201d, INGM, Via Francesco Sforza 35, 20122 Milan, Italy"},{"name":"DBS, University of Milan, Via Celoria 26, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Manfrini","sequence":"additional","affiliation":[{"name":"National Institute of Molecular Genetics, \u201cFondazione Romeo ed Enrica Invernizzi\u201d, INGM, Via Francesco Sforza 35, 20122 Milan, Italy"},{"name":"DBS, University of Milan, Via Celoria 26, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Oliveto","sequence":"additional","affiliation":[{"name":"National Institute of Molecular Genetics, \u201cFondazione Romeo ed Enrica Invernizzi\u201d, INGM, Via Francesco Sforza 35, 20122 Milan, Italy"},{"name":"DBS, University of Milan, Via Celoria 26, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Ricciardi","sequence":"additional","affiliation":[{"name":"National Institute of Molecular Genetics, \u201cFondazione Romeo ed Enrica Invernizzi\u201d, INGM, Via Francesco Sforza 35, 20122 Milan, Italy"},{"name":"DBS, University of Milan, Via Celoria 26, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"Grifantini","sequence":"additional","affiliation":[{"name":"National Institute of Molecular Genetics, \u201cFondazione Romeo ed Enrica Invernizzi\u201d, INGM, Via Francesco Sforza 35, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Degano","sequence":"additional","affiliation":[{"name":"Biocrystallography Unit, Dept. of Immunology, Transplantation and Infectious Diseases, IRCCS Scientific Institute San Raffaele, Via Olgettina 58, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Bresciani","sequence":"additional","affiliation":[{"name":"Department of Translational and Discovery Research, IRBM S.p.A., Via Pontina km 30, 600, 00071 Pomezia (Roma), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Biffo","sequence":"additional","affiliation":[{"name":"National Institute of Molecular Genetics, \u201cFondazione Romeo ed Enrica Invernizzi\u201d, INGM, Via Francesco Sforza 35, 20122 Milan, Italy"},{"name":"DBS, University of Milan, Via Celoria 26, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hershey, J.W.B., Sonenberg, N., and Mathews, M.B. 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