{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T11:16:29Z","timestamp":1760267789653,"version":"build-2065373602"},"reference-count":60,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T00:00:00Z","timestamp":1632355200000},"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":["2017R1E1A1A01074504","2019R1A2C1089145","2020R1A2C2012347"],"award-info":[{"award-number":["2017R1E1A1A01074504","2019R1A2C1089145","2020R1A2C2012347"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003645","name":"National Cancer Center","doi-asserted-by":"publisher","award":["NCC-2010273","NCC-2010320"],"award-info":[{"award-number":["NCC-2010273","NCC-2010320"]}],"id":[{"id":"10.13039\/501100003645","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003715","name":"Korea Research Institute of Bioscience and Biotechnology","doi-asserted-by":"publisher","award":["KGM5522113","KGS1082113","KGS1432113"],"award-info":[{"award-number":["KGM5522113","KGS1082113","KGS1432113"]}],"id":[{"id":"10.13039\/501100003715","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Spinal muscular atrophy (SMA) is caused by homozygous survival of motor neurons 1 (SMN1) gene deletion, leaving a duplicate gene, SMN2, as the sole source of SMN protein. However, a defect in SMN2 splicing, involving exon 7 skipping, results in a low level of functional SMN protein. Therefore, the upregulation of SMN protein expression from the SMN2 gene is generally considered to be one of the best therapeutic strategies to treat SMA. Most of the SMA drug discovery is based on synthetic compounds, and very few natural compounds have been explored thus far. Here, we performed an unbiased mechanism-independent and image-based screen of a library of microbial metabolites in SMA fibroblasts using an SMN-specific immunoassay. In doing so, we identified brefeldin A (BFA), a well-known inhibitor of ER-Golgi protein trafficking, as a strong inducer of SMN protein. The profound increase in SMN protein was attributed to, in part, the rescue of the SMN2 pre-mRNA splicing defect. Intriguingly, BFA increased the intracellular calcium concentration, and the BFA-induced exon 7 inclusion of SMN2 splicing, was abrogated by the depletion of intracellular calcium and by the pharmacological inhibition of calcium\/calmodulin-dependent kinases (CaMKs). Moreover, BFA considerably reduced the expression of Tra2-\u03b2 and SRSF9 proteins in SMA fibroblasts and enhanced the binding of PSF and hnRNP M to an exonic splicing enhancer (ESE) of exon 7. Together, our results demonstrate a significant role for calcium and its signaling on the regulation of SMN splicing, probably through modulating the expression\/activity of splicing factors.<\/jats:p>","DOI":"10.3390\/ijms221910234","type":"journal-article","created":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T09:59:15Z","timestamp":1632391155000},"page":"10234","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Regulation of Survival Motor Neuron Gene Expression by Calcium Signaling"],"prefix":"10.3390","volume":"22","author":[{"given":"Kwangman","family":"Choi","sequence":"first","affiliation":[{"name":"Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Korea"},{"name":"Department of Medical Biotechnology, SoonChunHyang  University, Asan 31538, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ansook","family":"Yang","sequence":"additional","affiliation":[{"name":"Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Korea"},{"name":"College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiyeon","family":"Baek","sequence":"additional","affiliation":[{"name":"Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Korea"},{"name":"College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyejeong","family":"Jeong","sequence":"additional","affiliation":[{"name":"Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Korea"},{"name":"College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yura","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Korea"},{"name":"Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Woosun","family":"Baek","sequence":"additional","affiliation":[{"name":"Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Korea"},{"name":"Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joon-Chul","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chungnam National University, Daejeon 34134, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingu","family":"Kang","sequence":"additional","affiliation":[{"name":"Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Korea"},{"name":"College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miri","family":"Choi","sequence":"additional","affiliation":[{"name":"Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Korea"},{"name":"College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youngwook","family":"Ham","sequence":"additional","affiliation":[{"name":"Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Korea"},{"name":"Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4228-7981","authenticated-orcid":false,"given":"Min-Jeong","family":"Son","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chungnam National University, Daejeon 34134, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6656-6523","authenticated-orcid":false,"given":"Sang-Bae","family":"Han","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3227-958X","authenticated-orcid":false,"given":"Janghwan","family":"Kim","sequence":"additional","affiliation":[{"name":"Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4363-4252","authenticated-orcid":false,"given":"Jae-Hyuk","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea"},{"name":"Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5166-4358","authenticated-orcid":false,"given":"Jong Seog","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea"},{"name":"Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haihong","family":"Shen","sequence":"additional","affiliation":[{"name":"Gwangju Institute of Science and Technology, School of life Sciences, Gwangju 61005, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sun-Hee","family":"Woo","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chungnam National University, Daejeon 34134, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1091-8099","authenticated-orcid":false,"given":"Jong Heon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Korea"},{"name":"Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7627-978X","authenticated-orcid":false,"given":"Sungchan","family":"Cho","sequence":"additional","affiliation":[{"name":"Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Korea"},{"name":"Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1055\/s-2001-15264","article-title":"Spinal muscular atrophy","volume":"21","author":"Talbot","year":"2001","journal-title":"Semin. 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