The splicing activator DAZAP1 integrates splicing control into MEK/Erk-regulated cell proliferation and migration.
The splicing activator DAZAP1 integrates splicing control into MEK/Erk-regulated cell proliferation and migration.
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DOI：
10.1038/ncomms4078
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发表时间：
2014
影响因子：
16.6
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Choudhury R;Roy SG;Tsai YS;Tripathy A;Graves LM;Wang Z
前体mRNA的选择性剪接是基因调控响应环境刺激的关键阶段。在这里，我们表明，DAZAP 1，RNA结合蛋白参与哺乳动物的发育和精子发生，促进列入弱外显子通过特异性识别不同的顺式元件。DAZAP 1的C-末端富含脯氨酸的结构域与一般剪接抑制剂相互作用并中和，并且当募集到前体mRNA时足以激活剪接。该结构域被MEK/Erk途径磷酸化，并且这种修饰对于DAZAP 1的剪接调节活性和核/胞质易位是必需的。使用mRNA-seq，我们鉴定了DAZAP 1调节的内源性剪接事件，其中许多参与维持细胞生长。DAZAP 1的敲低或过表达导致细胞增殖缺陷。总之，这些研究揭示了整合剪接控制到MEK/Erk调节的细胞增殖的分子机制。
Alternative splicing of pre-mRNA is a critical stage of gene regulation in response to environmental stimuli. Here we show that DAZAP1, an RNA binding protein involved in mammalian development and spermatogenesis, promotes inclusion of weak exons through specific recognition of diverse cis-elements. The C-terminal proline-rich domain of DAZAP1 interacts with and neutralizes general splicing inhibitors, and is sufficient to activate splicing when recruited to pre-mRNA. This domain is phosphorylated by the MEK/Erk pathway and this modification is essential for the splicing regulatory activity and the nuclear/cytoplasmic translocation of DAZAP1. Using mRNA-seq we identify endogenous splicing events regulated by DAZAP1, many of which are involved in maintaining cell growth. Knockdown or over-expression of DAZAP1 causes a cell proliferation defect. Taken together, these studies reveal a molecular mechanism that integrates splicing control into MEK/Erk regulated cell proliferation.
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影响因子：
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