Identification of a novel function of CX-4945 as a splicing regulator.
Identification of a novel function of CX-4945 as a splicing regulator.
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DOI：
10.1371/journal.pone.0094978
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Cho S
中科院分区：
文献类型：
--
作者：
Kim H;Choi K;Kang H;Lee SY;Chi SW;Lee MS;Song J;Im D;Choi Y;Cho S
选择性剪接是一种几乎无处不在的多功能过程，它控制基因表达，并从单个基因中产生具有不同功能的许多蛋白质异构体。选择性剪接的重要性已经被越来越多的人类疾病所证实，这些疾病是由剪接事件的错误调节引起的。然而，很少有化合物被报道作为选择性剪接的抑制剂，其潜在的临床应用需要进行评估。在这里，我们报告说，CX-4945是一种先前已充分表征的酪蛋白激酶2（CK 2）抑制剂，也是一种目前正在进行癌症治疗临床试验（II期）的分子，它以不依赖CK 2的方式调节哺乳动物细胞的剪接。使用外显子阵列的全转录组分析也显示了许多基因的选择性剪接的广泛改变。我们发现CX-4945在体外有效地抑制Cdc 2样激酶（Clks），进而抑制哺乳动物细胞中富含丝氨酸/丝氨酸（SR）蛋白的磷酸化。令人惊讶的是，CX-4945对Clks的总体功效（IC 50 = 3-90 nM）强于迄今报道的最强抑制剂TG-003。 在Clks中，Clk 2以ATP竞争性方式被CX-4945最强烈地抑制。我们的研究揭示了候选药物CX-4945作为一种有效的剪接调节剂的意想不到的活性，也表明了治疗异常剪接引起的疾病的潜在应用。
Alternative splicing is a nearly ubiquitous versatile process that controls gene expression and creates numerous protein isoforms with different functions from a single gene. The significance of alternative splicing has been confirmed by the increasing number of human diseases that are caused by misregulation of splicing events. Very few compounds, however, have been reported to act as inhibitors of alternative splicing, and their potential clinical use needs to be evaluated. Here, we report that CX-4945, a previously well-characterized inhibitor of casein kinase 2 (CK2) and a molecule currently in clinical trials (Phase II) for cancer treatment, regulates splicing in mammalian cells in a CK2-independent manner. Transcriptome-wide analysis using exon array also showed a widespread alteration in alternative splicing of numerous genes. We found that CX-4945 potently inhibits the Cdc2-like kinases (Clks) in vitro and in turn, leads to suppression of the phosphorylation of serine/arginine-rich (SR) proteins in mammalian cells. Surprisingly, the overall efficacy of CX-4945 on Clks (IC50 = 3–90 nM) was stronger than that of TG-003, the strongest inhibitor reported to date. Of the Clks, Clk2 was most strongly inhibited by CX-4945 in an ATP-competitive manner. Our research revealed an unexpected activity of the drug candidate CX-4945 as a potent splicing modulator and also suggested a potential application for therapy of diseases caused by abnormal splicing.
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影响因子：
12.4
作者：
Di Maira, G;Salvi, M;Ruzzene, M
通讯作者：
Ruzzene, M
DOI：
10.1007/978-0-387-77374-2_8
发表时间：
2007-01-01
期刊：
ALTERNATIVE SPLICING IN THE POSTGENOMIC ERA
影响因子：
--
作者：
Martinez-Contreras, Rebeca;Cloutier, Philippe;Chabot, Benoit
通讯作者：
Chabot, Benoit
影响因子：
2.7
作者：
Coombs, Thomas C.;Tanega, Cordelle;Aube, Jeffrey
通讯作者：
Aube, Jeffrey
影响因子：
3.5
作者：
Ferguson, Andrew D.;Sheth, Payal R.;Le, Hung V.
通讯作者：
Le, Hung V.
DOI：
10.1006/bbrc.1997.7913
发表时间：
1998-01-14
影响因子：
3.1
作者：
Kuroyanagi, N;Onogi, H;Hagiwara, M
通讯作者：
Hagiwara, M