Regulation of Survival Motor Neuron Gene Expression by Calcium Signaling
| Autor: | Hyejeong Jeong, Sang-Bae Han, Kwangman Choi, Janghwan Kim, Woosun Baek, Joon-Chul Kim, Jong Seog Ahn, Mingu Kang, Ansook Yang, Sun-Hee Woo, Min-Jeong Son, Haihong Shen, Sungchan Cho, Youngwook Ham, Jong Heon Kim, Jiyeon Baek, Jae-Hyuk Jang, Miri Choi, Yura Kang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
spinal muscular atrophy (SMA)
QH301-705.5 RNA Splicing Exonic splicing enhancer Gene Expression Golgi Apparatus SMN1 calcium signaling Endoplasmic Reticulum Catalysis Article Cell Line Inorganic Chemistry Muscular Atrophy Spinal Exon Gene expression medicine Humans RNA Messenger Biology (General) Physical and Theoretical Chemistry QD1-999 Molecular Biology Spectroscopy brefeldin A (BFA) Calcium signaling Motor Neurons Chemistry Organic Chemistry SMN Complex Proteins General Medicine Spinal muscular atrophy neuromuscular disease Exons Fibroblasts SMA medicine.disease Computer Science Applications Cell biology nervous system diseases SMN Protein Transport HEK293 Cells splicing modulator RNA splicing pre-mRNA splicing |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 19 International Journal of Molecular Sciences, Vol 22, Iss 10234, p 10234 (2021) |
| ISSN: | 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
| Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |