Regulation of the alternative splicing of sarcoplasmic reticulum Ca^<2+>-AT Pase1 (SERCA1) by phorbol 12-myristate 13-acetate (PMA) via a PKC pathway.
Regulation of the alternative splicing of sarcoplasmic reticulum Ca^<2+>-AT Pase1 (SERCA1) by phorbol 12-myristate 13-acetate (PMA) via a PKC pathway.
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佛波醇12-肉豆蔻酸酯13-乙酸酯(PMA)通过PKC途径调节肌浆网Ca^2-AT Pase1(SERCA1)的选择性剪接。
DOI：
10.1016/j.bbrc.2012.05.033
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发表时间：
2012
影响因子：
3.1
通讯作者：
Ishiura S.
中科院分区：
文献类型：
--
作者：
Zhao Y;Koebis M;Suo S;Ohno S;Ishiura S.
1型肌强直性营养不良症（DM1）是一种多系统疾病，迄今尚无明确的治疗方法。可渗透细胞的小分子具有治疗DM1的潜力。在这项研究中，我们研究了蛋白激酶C （PKC）信号传导与肌浆网Ca2+-ATPase1 （SERCA1）剪接之间的关系。我们的目的是阐明选择性剪接调控的机制，以探索DM1的新治疗策略。通过评估内源性SERCA1基因在HEK293细胞中的剪接模式，我们发现用phorbol 12-肉豆酸酯13-乙酸酯（PMA）处理可以调节SERCA1剪接。有趣的是，PMA处理48小时使SERCA1剪接正常化，而处理1.5小时则促进了异常剪接。这两种反应表现出剂量依赖性，并被PKC抑制剂Ro 31-8220完全消除。此外，RNAi对PKCβII和PKCθ的抑制与长时间PMA治疗相似。这些结果表明PKC信号参与了SERCA1的剪接，并为选择性剪接与PKC信号之间的联系提供了新的证据。
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 Ca2+-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 48h 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.