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dc.contributor.authorChen, Yu-Chiaen_US
dc.contributor.authorChang, Jan-Gowthen_US
dc.contributor.authorLiu, Ting-Yuanen_US
dc.contributor.authorJong, Yuh-Jyhen_US
dc.contributor.authorCheng, Wei-Linen_US
dc.contributor.authorYuo, Chung-Yeeen_US
dc.date.accessioned2017-04-21T06:56:34Z-
dc.date.available2017-04-21T06:56:34Z-
dc.date.issued2017-04en_US
dc.identifier.issn0753-3322en_US
dc.identifier.urihttp://dx.doi.org/10.1016/j.biopha.2017.01.104en_US
dc.identifier.urihttp://hdl.handle.net/11536/133124-
dc.description.abstractSpinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron gene (SMN1) on chromosome 5q13. A second copy of the SMN gene (SMN2) also exists on chromosome 5, and both genes can produce functional protein. However, due to alternative splicing of the exon 7, the majority of SMN protein produced by SMN2 is truncated and unable to compensate for the loss of SMN1. Increasing full-length SMN protein production by promoting the exon 7 inclusion in SMN2 mRNA or increasing SMN2 gene transcription could be a therapeutic approach for SMA. In this study, we screened for the compounds that enhance SMN2 exon 7 inclusion by using SMN2 minigene-luciferase reporter system. We found that securinine can increase luciferase activity, indicating that securinine promoted SMN2 exon 7 inclusion. In addition, securinine increased full-length SMN2 mRNA and SMN protein expression in SMA patient-derived lymphoid cell lines. To investigate the mechanism of securinine effect on SMN2 splicing, we compared the protein levels of relevant splicing factors between securinine-treated and untreated cells. We found that securinine downregulated hnRNP A1 and Sam68 and upregulated Tra2-b1 expression. However, securinine, unlike HDAC inhibitors, did not enhance tra2-b1 gene transcription, indicating a post-transcriptional mechanism for Tra2-b1 upregulation. Furthermore, we treated SMA-like mice with securinine by i.p. injection and found that securinine treatment increased SMN2 exon 7 inclusion and SMN protein expression in the brain and spinal cord. According to our results, securinine might have the potential to become a therapeutic drug for SMA disease. (C) 2017 Elsevier Masson SAS. All rights reserved.en_US
dc.language.isoen_USen_US
dc.subjectSpinal muscular atrophyen_US
dc.subjectSurvival motor neuron geneen_US
dc.subjectSecurinineen_US
dc.subjectTra2-beta1en_US
dc.titleSecurinine enhances SMN2 exon 7 inclusion in spinal muscular atrophy cellsen_US
dc.identifier.doi10.1016/j.biopha.2017.01.104en_US
dc.identifier.journalBIOMEDICINE & PHARMACOTHERAPYen_US
dc.citation.volume88en_US
dc.citation.spage708en_US
dc.citation.epage714en_US
dc.contributor.department生物科技學系zh_TW
dc.contributor.departmentDepartment of Biological Science and Technologyen_US
dc.identifier.wosnumberWOS:000395528000083en_US
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