title: Regulation of the alternative splicing of sarcoplasmic reticulum Ca²⁺-ATPase1 (SERCA1) by phorbol 12-myristate 13-acetate (PMA) via a PKC pathway.
abstract: Myotonic dystrophy type 1 (DM1) is a multi-systemic disease with no established treatment to date. Small, cell-permeable molecules hold the potential to treat DM1. In this study, we investigated the association between protein kinase C (PKC) signaling and splicing of sarcoplasmic reticulum Ca(2+)-ATPase1 (SERCA1). Our aim was to clarify the mechanisms underlying the regulation of alternative splicing, in order to explore new therapeutic strategies for DM1. By assessing the splicing pattern of the endogenous SERCA1 gene in HEK293 cells, we found that treatment with phorbol 12-myristate 13-acetate (PMA) regulated SERCA1 splicing. Interestingly, treatment with PMA for 48 h normalized SERCA1 splicing, while treatment for 1.5h promoted aberrant splicing. These two responses showed dose dependency and were completely abolished by the PKC inhibitor Ro 31-8220. Furthermore, repression of PKCβII and PKCθ by RNAi mimicked prolonged PMA treatment. These results indicate that PKC signaling is involved in the splicing of SERCA1 and provide new evidence for a link between alternative splicing and PKC signaling.
authors.affiliation: Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan.
authors.forename: Yimeng
authors.initials: Y
authors.lastname: Zhao
authors.forename: Michinori
authors.initials: M
authors.lastname: Koebis
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suo
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohno
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ishiura
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects / Q000502:physiology*; D005091:Exons / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D009223:Myotonic Dystrophy / Q000201:enzymology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051745:Protein Kinase C-delta; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506943:ATP2A1 protein, human; D013755:Tetradecanoylphorbol Acetate; C064758:Ro 31-8220