Engineering splicing factors with designed specificities.
Engineering splicing factors with designed specificities.
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DOI：
10.1038/nmeth.1379
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发表时间：
2009-11
期刊：
影响因子：
48
通讯作者：
Wang, Zefeng
中科院分区：
文献类型：
--
作者：
Wang, Yang;Cheong, Cheom-Gil;Hall, Traci M. Tanaka;Wang, Zefeng
选择性剪接通常由特异性结合前mRNA以激活或抑制剪接反应的反式作用因子调节。这种调节对于正常的基因表达至关重要，剪接的失调与人类疾病密切相关。在这里，我们工程师人工剪接因子结合序列特异性RNA结合域的人Pumilio 1与功能域，调节剪接。我们应用这些因子来调节所选靶点中不同类型的选择性剪接，检查来自天然剪接因子的效应结构域的活性，并调节内源性基因Bcl-x（一种抗癌靶点）的剪接。靶向Bcl-x的设计因子增加了促凋亡Bcl-xS剪接同种型，从而促进了细胞凋亡并增加了癌细胞对常见抗肿瘤药物的化学敏感性。我们的方法允许创建人工因子来靶向几乎任何前mRNA，为研究剪接调控和操纵疾病相关剪接事件提供了新的策略。
Alternative splicing is generally regulated by trans-acting factors that specifically bind pre-mRNA to activate or inhibit the splicing reaction. This regulation is critical for normal gene expression, and dysregulation of splicing is closely associated with human diseases. Here we engineer artificial splicing factors by combining sequence-specific RNA-binding domains of human Pumilio1 with functional domains that regulate splicing. We applied these factors to modulate different types of alternative splicing in selected targets, examine the activity of effector domains from natural splicing factors, and modulate splicing of an endogenous gene, Bcl-x, an anti-cancer target. The designer factor targeted to Bcl-x increased the pro-apoptotic Bcl-xS splicing isoform, thus promoting apoptosis and increasing chemosensitivity of cancer cells to common anti-tumor drugs. Our approach permits the creation of artificial factors to target virtually any pre-mRNA, providing a new strategy to study splicing regulation and manipulate disease-associated splicing events.
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影响因子：
64.5
作者：
Cooper TA;Wan L;Dreyfuss G
通讯作者：
Dreyfuss G
影响因子：
4.8
作者：
Hutchison, S;LeBel, C;Chabot, B
通讯作者：
Chabot, B
影响因子：
64.5
作者：
Wang, XQ;McLachlan, J;Hall, TMT
通讯作者：
Hall, TMT
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：
14.9
作者：
Wilusz, JE;Devanney, SC;Caputi, M
通讯作者：
Caputi, M