{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T19:13:59Z","timestamp":1768677239350,"version":"3.49.0"},"reference-count":47,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2013,6,3]],"date-time":"2013-06-03T00:00:00Z","timestamp":1370217600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:p>Bim is a member of the pro\u2010apoptotic BH3\u2010only Bcl\u20102 family of proteins. <jats:styled-content style=\"fixed-case\"><jats:italic>Bim<\/jats:italic><\/jats:styled-content> gene undergoes alternative splicing to produce three predominant splicing variants (BimEL, BimL and BimS). The smallest variant BimS is the most potent inducer of apoptosis. Zinc (Zn<jats:sup>2+<\/jats:sup>) has been reported to stimulate apoptosis in various cell types. In this study, we examined whether Zn<jats:sup>2+<\/jats:sup> affects the expression of Bim in human neuroblastoma SH\u2010SY5Y cells. Zn<jats:sup>2+<\/jats:sup> triggered alterations in Bim splicing and induced preferential generation of BimS, but not BimEL and BimL, in a dose\u2010 and time\u2010dependent manner. Other metals (cadmium, cobalt and copper) and stresses (oxidative, endoplasmic reticulum and genotoxic stresses) had little or no effect on the expression of BimS. To address the mechanism of Zn<jats:sup>2+<\/jats:sup>\u2010induced preferential generation of BimS, which lacks exon\u00a04, we developed a <jats:styled-content style=\"fixed-case\"><jats:italic>Bim<\/jats:italic><\/jats:styled-content> mini\u2010gene construct. Deletion analysis using the <jats:styled-content style=\"fixed-case\"><jats:italic>Bim<\/jats:italic><\/jats:styled-content> mini\u2010gene revealed that predicted binding sites of the <jats:styled-content style=\"fixed-case\">SR<\/jats:styled-content> protein <jats:styled-content style=\"fixed-case\">SRSF<\/jats:styled-content>6, also known as <jats:styled-content style=\"fixed-case\">SR<\/jats:styled-content>p55, are located in the intronic region adjacent to exon\u00a04. We also found that mutations in the predicted <jats:styled-content style=\"fixed-case\">SRSF<\/jats:styled-content>6\u2010binding sites abolished generation of BimS m<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> from the mutated <jats:italic>Bim<\/jats:italic> mini\u2010gene. In addition, a <jats:styled-content style=\"fixed-case\">UV<\/jats:styled-content> cross\u2010linking assay followed by Western blotting showed that SRSF6 directly bound to the predicted binding site and Zn<jats:sup>2+<\/jats:sup> suppressed this binding. Moreover, Zn<jats:sup>2+<\/jats:sup> stimulated SRSF6 hyper\u2010phosphorylation. TG003, a cdc2\u2010like kinase inhibitor, partially prevented Zn<jats:sup>2+<\/jats:sup>\u2010induced generation of BimS and SRSF6 hyper\u2010phosphorylation. Taken together, our findings suggest that Zn<jats:sup>2+<\/jats:sup> inhibits the activity of SRSF6 and promotes elimination of exon\u00a04, leading to preferential generation of BimS.<\/jats:p>","DOI":"10.1111\/febs.12318","type":"journal-article","created":{"date-parts":[[2013,5,4]],"date-time":"2013-05-04T16:58:09Z","timestamp":1367686689000},"page":"3313-3327","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Zinc\u2010induced modulation of <scp>SRSF<\/scp>6 activity alters Bim splicing to promote generation of the most potent apoptotic isoform BimS"],"prefix":"10.1111","volume":"280","author":[{"given":"Hirokazu","family":"Hara","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Pharmaceutics Gifu Pharmaceutical University Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuya","family":"Takeda","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical 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