Wrenchnolol Derivative Optimized for Gene Activation in Cells
Wrenchnolol Derivative Optimized for Gene Activation in Cells
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DOI：
10.1021/ja900669k
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发表时间：
2009-04-08
影响因子：
15
通讯作者：
Uesugi, Motonari
中科院分区：
文献类型：
--
作者：
Jung, Dongju;Shimogawa, Hiroki;Uesugi, Motonari
自然产生的转录因子通常有两个独立的结构域，一个是DNA结合域，一个是激活域。在设计模仿转录因子的合成小分子时，这两个结构域中的每一个都需要被小分子对应的结构域所取代。本研究的结果表明，wrenchnolol的衍生物，一种与SuR-2共激活剂相互作用的合成分子，在体外和细胞内作为激活模块，当被拴在DNA结合分子上时，刺激基因转录。用化学方法合成了13种核仁酚衍生物，并对它们在体外和细胞内激活转录的能力进行了测试。当连接到GAL4 DNA结合域时，一种衍生物增加了细胞9-Tell中GAL4反应报告基因的转录。当与生肌转录因子MyoD的DNA结合域连接时，这种优化的衍生物还可以诱导高达45%的C2C12细胞的肌肉发生。这种优化的衍生品可以作为设计生物工具或全合成转录因子组件的起点，允许选择性上调基因。
Naturally occurring transcription factors usually have two independent domains, a DNA-binding domain and an activation domain. In designing a synthetic small molecule that mimics a transcription factor, each of the two domains needs to be replaced by small-molecule counterparts. Results of the present study show that derivatives of wrenchnolol, a synthetic molecule that interacts with Sur-2 coactivator, serve as activation modules and stimulate gene transcription in vitro and in cells when tethered to a DNA-binding molecule. Thirteen derivatives of wrenchnolol were chemically synthesized and tested for their ability to activate transcription in vitro and in cells. When tethered to the GAL4 DNA-binding domain, one derivative increased transcription of a GAL4-responsive reporter gene in cells 9-told. This optimized derivative also induced up to 45% myogenesis of C2C12 cells when tethered to the DNA-binding domain of myogenic transcription factor MyoD. This optimized derivative may serve as a starting point for designing biological tools or components of fully synthetic transcription factors that permit selective up-regulation of genes.