The biflavonoid isoginkgetin is a general inhibitor of Pre-mRNA splicing.
The biflavonoid isoginkgetin is a general inhibitor of Pre-mRNA splicing.
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DOI：
10.1074/jbc.m805556200
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发表时间：
2008-11-28
期刊：
影响因子：
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通讯作者：
Moore MJ
中科院分区：
文献类型：
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作者：
O'Brien K;Matlin AJ;Lowell AM;Moore MJ
可逆地抑制基因表达中的特定步骤的膜可渗透化合物是用于细胞生物学和生物化学/结构研究的非常有用的工具。与可使用多种小分子效应物的其他基因表达步骤相比，很少有化合物被描述为前体mRNA剪接的一般抑制剂。在这里，我们报告的建设和验证的一组哺乳动物细胞系适用于识别小分子抑制剂的前mRNA剪接。 使用这些细胞系，我们确定了天然产物isoginkgetin作为一种通用的抑制剂的主要和次要的剪接体。异银杏黄酮在相似的微摩尔浓度下抑制体内和体外剪接。它似乎是通过阻止U4/U 5/U6三小核核糖核蛋白的稳定募集，导致前剪接体A复合物的积累来实现的。像其他两个最近报道的一般前mRNA剪接抑制剂，异银杏黄酮先前已被描述为抗肿瘤剂。我们的研究结果表明，剪接抑制是异银杏黄酮抗肿瘤活性的机制基础。因此，前体mRNA剪接抑制剂可能代表了开发新抗癌剂的新途径。
Membrane-permeable compounds that reversibly inhibit a particular step in gene expression are highly useful tools for cell biological and biochemical/structural studies. In comparison with other gene expression steps where multiple small molecule effectors are available, very few compounds have been described that act as general inhibitors of pre-mRNA splicing. Here we report construction and validation of a set of mammalian cell lines suitable for the identification of small molecule inhibitors of pre-mRNA splicing. Using these cell lines, we identified the natural product isoginkgetin as a general inhibitor of both the major and minor spliceosomes. Isoginkgetin inhibits splicing both in vivo and in vitro at similar micromolar concentrations. It appears to do so by preventing stable recruitment of the U4/U5/U6 tri-small nuclear ribonucleoprotein, resulting in accumulation of the prespliceosomal A complex. Like two other recently reported general pre-mRNA splicing inhibitors, isoginkgetin has been previously described as an anti-tumor agent. Our results suggest that splicing inhibition is the mechanistic basis of the anti-tumor activity of isoginkgetin. Thus, pre-mRNA splicing inhibitors may represent a novel avenue for development of new anti-cancer agents.