{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:08:43Z","timestamp":1787314123396,"version":"build-2736575974"},"reference-count":52,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"840","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2024,6,11]]},"abstract":"<jats:p>\n                    Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Inactivating mutations and\/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumors are associated with an increased risk of metastasis. To investigate the mechanisms underlying this risk, we explored the functional consequences of BAP1 deficiency. UM cell lines expressing mutant\n                    <jats:italic>BAP1<\/jats:italic>\n                    grew more slowly than those expressing wild-type\n                    <jats:italic>BAP1<\/jats:italic>\n                    in culture and in vivo. The ability of BAP1 reconstitution to restore cell proliferation in BAP1-deficient cells required its deubiquitylase activity. Proteomic analysis showed that BAP1-deficient cells had decreased phosphorylation of ribosomal S6 and its upstream regulator, p70S6K1, compared with both wild-type and BAP1 reconstituted cells. In turn, expression of p70S6K1 increased S6 phosphorylation and proliferation of BAP1-deficient UM cells. Consistent with these findings,\n                    <jats:italic>BAP1<\/jats:italic>\n                    mutant primary UM tumors expressed lower amounts of p70S6K1 target genes, and S6 phosphorylation was decreased in\n                    <jats:italic>BAP1<\/jats:italic>\n                    mutant patient-derived xenografts (PDXs), which grew more slowly than wild-type PDXs in the liver (the main metastatic site of UM) in mice. BAP1-deficient UM cells were also more resistant to amino acid starvation, which was associated with diminished phosphorylation of S6. These studies demonstrate that BAP1 deficiency slows the proliferation of UM cells through regulation of S6 phosphorylation. These characteristics may be associated with metastasis by ensuring survival during amino acid starvation.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.adn8376","type":"journal-article","created":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T13:58:41Z","timestamp":1718114321000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":9,"title":["Slow proliferation of BAP1-deficient uveal melanoma cells is associated with reduced S6 signaling and resistance to nutrient stress"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1873-6820","authenticated-orcid":true,"given":"Vivian","family":"Chua","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107 USA."},{"name":"School of Medical and Health Sciences, Edith Cowan University, Joondalup, Perth, WA 6027 Australia."},{"name":"Centre for Precision Health, Edith Cowan University, Joondalup, Perth, WA 6027 Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melisa","family":"Lopez-Anton","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Department of Oncological Sciences, Black Family Stem Cell Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2672-9468","authenticated-orcid":true,"family":"Mizue Terai","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 19107 USA."},{"name":"Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107 USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1562-4049","authenticated-orcid":true,"family":"Ryota Tanaka","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 19107 USA."},{"name":"Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University, Osaka, 545-8585 Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Usman","family":"Baqai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107 USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7053-8039","authenticated-orcid":true,"given":"Timothy J.","family":"Purwin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107 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USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2894-202X","authenticated-orcid":true,"given":"Kristine","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107 USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6032-2959","authenticated-orcid":true,"given":"Rohith","family":"Tudi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107 USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Jeon","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107 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Cancer Center, Houston, TX 77030 USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6694-6507","authenticated-orcid":true,"given":"Julio A.","family":"Aguirre-Ghiso","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461 USA."},{"name":"Cancer Dormancy and Tumor Microenvironment Institute, Albert Einstein College of Medicine, Bronx, NY 10461 USA."},{"name":"Montefiore Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461 USA."},{"name":"Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY 10461 USA."},{"name":"Ruth L. and David S. 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