Regulation of survival motor neuron gene expression by calcium signaling = 척수성 근위축증 원인 유전자인 SMN의 칼슘의존적 발현조절

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Regulation of survival motor neuron gene expression by calcium signaling = 척수성 근위축증 원인 유전자인 SMN의 칼슘의존적 발현조절
Kwangman Choi; Ansook Yang; Jiyeon Baek; HyeJeong Jeong; Y Kang; W Baek; J C Kim; Mingu Kang; Miri Choi; Youngwook Ham; M J Son; S B Han; Janghwan KimJae-Hyuk JangJong Seog Ahn; H Shen; S H Woo; J H Kim; Sungchan Cho
Bibliographic Citation
International Journal of Molecular Sciences, vol. 22, no. 19, pp. 10234-10234
Publication Year
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-β 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.
Spinal muscular atrophy (SMA)Neuromuscular diseaseSMNpre-mRNA splicingSplicing modulatorCalcium signalingBrefeldin A (BFA)
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Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
Ochang Branch Institute > Chemical Biology Research Center > 1. Journal Articles
Ochang Branch Institute > Nucleic Acid Therapeutics Research Center > 1. Journal Articles
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