{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T04:41:08Z","timestamp":1784263268403,"version":"3.55.0"},"reference-count":41,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,19]],"date-time":"2020-10-19T00:00:00Z","timestamp":1603065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2017R1A2B2005508 and 2019R1A2C1086949"],"award-info":[{"award-number":["2017R1A2B2005508 and 2019R1A2C1086949"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008783","name":"National Research Council of Science and Technology","doi-asserted-by":"publisher","award":["CAP-15-03-KRIBB"],"award-info":[{"award-number":["CAP-15-03-KRIBB"]}],"id":[{"id":"10.13039\/501100008783","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>BCL-2 interacting cell death suppressor (BIS), also known as BAG3, is a multifunctional protein. Aberrant expression and mutation of BIS have been implicated in cancers and myopathy. However, there have only been a few studies on the splicing of BIS pre-mRNA. In the present study, through RT-PCR and sequencing in various cell lines and mouse tissues, we identified for the first time the presence of BIS mRNA isomers in which exon 3 or exons 2\u20133 are skipped. We also demonstrated that the depletion of SRSF3 promoted the skipping of exon 3 of BIS pre-mRNA in endogenous BIS and the GFP-BIS minigene. SRSF3 specifically interacts with the putative binding sites in exon 3, in which deletion promoted the skipping of exon 3 in the GFP-BIS minigene, which was comparable to the effect of SRSF knockdown. Even though acceleration of exon 3 skipping was not observed in response to various stimuli, SRSF3 depletion, accompanied by the production of a truncated BIS protein, inhibited the nuclear translocation of HSF1, which was restored by the wild-type BIS, not by exon 3-depleted BIS. Therefore, our results suggested that the maintenance of SRSF3 levels and subsequent preservation of the intact BIS protein is an important factor in modulating HSF1 localization upon cellular stress.<\/jats:p>","DOI":"10.3390\/cells9102325","type":"journal-article","created":{"date-parts":[[2020,10,19]],"date-time":"2020-10-19T20:44:41Z","timestamp":1603140281000},"page":"2325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["SRSF3 Is a Critical Requirement for Inclusion of Exon 3 of BIS Pre-mRNA"],"prefix":"10.3390","volume":"9","author":[{"given":"Ji-Ye","family":"Baek","sequence":"first","affiliation":[{"name":"Department of Biochemistry, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"},{"name":"Institute of Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"},{"name":"Department of Biomedicine &amp; Health Sciences, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye-Hyeon","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"},{"name":"Institute of Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soon-Young","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"},{"name":"Institute of Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeehan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"},{"name":"Institute of Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"},{"name":"Department of Biomedicine &amp; Health Sciences, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyunghyun","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"},{"name":"Institute of Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"},{"name":"Department of Biomedicine &amp; Health Sciences, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5970-194X","authenticated-orcid":false,"given":"Jeong-Hwa","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"},{"name":"Institute of Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3389\/fnmol.2017.00177","article-title":"The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease","volume":"10","author":"Sturner","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6183","DOI":"10.1038\/sj.onc.1203043","article-title":"Bis, a Bcl-2-binding protein that synergizes with Bcl-2 in preventing cell death","volume":"18","author":"Lee","year":"1999","journal-title":"Oncogene"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e141","DOI":"10.1038\/cddis.2011.24","article-title":"BAG3: A multifaceted protein that regulates major cell pathways","volume":"2","author":"Rosati","year":"2011","journal-title":"Cell Death Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.jacbts.2017.09.009","article-title":"The Multifunctional Protein BAG3: A Novel Therapeutic Target in Cardiovascular Disease","volume":"3","author":"Myers","year":"2018","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.semcdb.2017.08.049","article-title":"Role of BAG3 in cancer progression: A therapeutic opportunity","volume":"78","author":"Basile","year":"2018","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"761","DOI":"10.2353\/ajpath.2006.060250","article-title":"BAG3 deficiency results in fulminant myopathy and early lethality","volume":"169","author":"Homma","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"403","DOI":"10.4196\/kjpp.2014.18.5.403","article-title":"Bis is Induced by Oxidative Stress via Activation of HSF1","volume":"18","author":"Yoo","year":"2014","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1002\/jcp.21397","article-title":"bag3 gene expression is regulated by heat shock factor 1","volume":"215","author":"Franceschelli","year":"2008","journal-title":"J. Cell Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1016\/j.biocel.2010.07.021","article-title":"Activation of heat shock factor 1 plays a role in pyrrolidine dithiocarbamate-mediated expression of the co-chaperone BAG3","volume":"42","author":"Song","year":"2010","journal-title":"Int J. Biochem. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1038\/leu.2010.68","article-title":"WT1 protein is a transcriptional activator of the antiapoptotic bag3 gene","volume":"24","author":"Cesaro","year":"2010","journal-title":"Leukemia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5011","DOI":"10.1038\/onc.2008.142","article-title":"Activation of BAG3 by Egr-1 in response to FGF-2 in neuroblastoma cells","volume":"27","author":"Gentilella","year":"2008","journal-title":"Oncogene"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1152\/physiolgenomics.00097.2007","article-title":"Transcriptional profiling of genes that are regulated by the endoplasmic reticulum-bound transcription factor AIbZIP\/CREB3L4 in prostate cells","volume":"31","author":"Lessard","year":"2007","journal-title":"Physiol. Genom."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3104","DOI":"10.4161\/cc.7.19.6774","article-title":"Identification of a synaptosome-associated form of BAG3 protein","volume":"7","author":"Bruno","year":"2008","journal-title":"Cell Cycle"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/j.bbrc.2008.02.112","article-title":"Caspase-dependent cleavage of BAG3 in proteasome inhibitors-induced apoptosis in thyroid cancer cells","volume":"369","author":"Du","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1002\/jcp.22097","article-title":"Characterization of BAG3 cleavage during apoptosis of pancreatic cancer cells","volume":"224","author":"Wang","year":"2010","journal-title":"J. Cell Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10252","DOI":"10.1158\/0008-5472.CAN-07-0618","article-title":"BAG3 regulates motility and adhesion of epithelial cancer cells","volume":"67","author":"Iwasaki","year":"2007","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e1537","DOI":"10.1038\/cddis.2014.501","article-title":"BIS targeting induces cellular senescence through the regulation of 14-3-3 zeta\/STAT3\/SKP2\/p27 in glioblastoma cells","volume":"5","author":"Lee","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e260","DOI":"10.1038\/emm.2016.84","article-title":"ERK-mediated phosphorylation of BIS regulates nuclear translocation of HSF1 under oxidative stress","volume":"48","author":"Kim","year":"2016","journal-title":"Exp. Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s13273-017-0010-0","article-title":"BIS overexpression does not affect the sensitivity of HEK 293T cells against apoptosis","volume":"13","author":"Baek","year":"2017","journal-title":"Mol. Cell Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/wrna.100","article-title":"Evolution of SR protein and hnRNP splicing regulatory factors","volume":"3","author":"Busch","year":"2012","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.14348\/molcells.2017.2319","article-title":"SR Proteins: Binders, Regulators, and Connectors of RNA","volume":"40","author":"Jeong","year":"2017","journal-title":"Mol. Cells"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nrm3525","article-title":"Alternative splicing: A pivotal step between eukaryotic transcription and translation","volume":"14","author":"Kornblihtt","year":"2013","journal-title":"Nat. Rev. Mol. Cell Bio."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2804","DOI":"10.1074\/mcp.M112.025882","article-title":"Bcl2-associated Athanogene 3 Interactome Analysis Reveals a New Role in Modulating Proteasome Activity","volume":"12","author":"Chen","year":"2013","journal-title":"Mol. Cell. Proteom."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Guisbert, K.S.K., and Guisbert, E. (2017). SF3B1 is a stress-sensitive splicing factor that regulates both HSF1 concentration and activity. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176382"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbrc.2013.05.027","article-title":"SRp20: An overview of its role in human diseases","volume":"436","author":"Corbo","year":"2013","journal-title":"Biochem. Bioph. Res. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2792","DOI":"10.1038\/onc.2012.288","article-title":"Downregulation of splicing factor SRSF3 induces p53 beta, an alternatively spliced isoform of p53 that promotes cellular senescence","volume":"32","author":"Tang","year":"2013","journal-title":"Oncogene"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"612","DOI":"10.5483\/BMBRep.2016.49.11.118","article-title":"SR proteins regulate V-6 exon splicing of CD44 pre-mRNA","volume":"49","author":"Loh","year":"2016","journal-title":"BMB Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"806","DOI":"10.7150\/ijbs.6.806","article-title":"SRp20 is a proto-oncogene critical for cell proliferation and tumor induction and maintenance","volume":"6","author":"Jia","year":"2010","journal-title":"Int. J. Biol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1128\/MCB.01709-08","article-title":"SRp20 and CUG-BP1 Modulate Insulin Receptor Exon 11 Alternative Splicing","volume":"29","author":"Sen","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1158\/1541-7786.MCR-12-0213","article-title":"Hepatocyte Growth Factor Enhances Alternative Splicing of the Kruppel-like Factor 6 (KLF6) Tumor Suppressor to Promote Growth through SRSF1","volume":"10","author":"Munoz","year":"2012","journal-title":"Mol. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5077","DOI":"10.1093\/emboj\/16.16.5077","article-title":"The splicing factor SRp20 modifies splicing of its own mRNA and ASF\/SF2 antagonizes this regulation","volume":"16","author":"Jumaa","year":"1997","journal-title":"EMBO J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"32943","DOI":"10.1074\/jbc.M301090200","article-title":"The CD44 alternative v9 exon contains a splicing enhancer responsive to the SR proteins 9G8, ASF\/SF2, and SRp20","volume":"278","author":"Lejeune","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"14548","DOI":"10.1038\/srep14548","article-title":"PTBP1 and PTBP2 impaired autoregulation of SRSF3 in cancer cells","volume":"5","author":"Guo","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3502","DOI":"10.7150\/jca.42645","article-title":"Aberrant expression and regulatory network of splicing factor-SRSF3 in tumors","volume":"11","author":"Che","year":"2020","journal-title":"J. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e94623","DOI":"10.1172\/jci.insight.94623","article-title":"A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress","volume":"2","author":"Judge","year":"2017","journal-title":"JCI Insight."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1002\/jcb.22343","article-title":"Autoregulation of Co-Chaperone BAG3 Gene Transcription","volume":"108","author":"Gentilella","year":"2009","journal-title":"J. Cell. Biochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s13273-016-0009-y","article-title":"Depletion of BIS sensitizes A549 cells to treatment with cisplatin","volume":"12","author":"Cui","year":"2016","journal-title":"Mol. Cell. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.bbrc.2015.07.006","article-title":"BAG3 affects the nucleocytoplasmic shuttling of HSF1 upon heat stress","volume":"464","author":"Jin","year":"2015","journal-title":"Biochem. Bioph. Res. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"C250","DOI":"10.1152\/ajpcell.00091.2013","article-title":"Oxidative stress-inducible truncated serine\/arginine-rich splicing factor 3 regulates interleukin-8 production in human colon cancer cells","volume":"306","author":"Kano","year":"2014","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"228","DOI":"10.2152\/jmi.60.228","article-title":"Truncated serine\/arginine-rich splicing factor 3 accelerates cell growth through up-regulating c-Jun expression","volume":"60","author":"Kano","year":"2013","journal-title":"J. Med. Invest."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1111\/acer.13474","article-title":"Alcohol-Mediated Missplicing of Mcl-1 Pre-mRNA is Involved in Neurotoxicity","volume":"41","author":"Sariyer","year":"2017","journal-title":"Alcohol. Clin. Exp. 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