A vertebrate RNA-binding protein Fox-1 regulates tissue-specific splicing via the pentanucleotide GCAUG
A vertebrate RNA-binding protein Fox-1 regulates tissue-specific splicing via the pentanucleotide GCAUG
复制标题
DOI：
10.1093/emboj/cdg089
复制
发表时间：
2003-02-17
期刊：
影响因子：
11.4
通讯作者：
Inoue, K
中科院分区：
文献类型：
--
作者：
Jin, Y;Suzuki, H;Inoue, K
选择性剪接是真核生物基因表达调控的重要机制之一。在这里，我们报告了一种组织特异性RNA结合蛋白，Fox-1，它调节脊椎动物的选择性剪接。Fox-1在体外与五核苷酸GCAUG特异性结合。在斑马鱼和小鼠中，fox-1在心脏和骨骼肌中表达。作为Fox-1的肌肉特异性靶点的候选者，我们考虑了两个基因，即人线粒体ATP合成酶γ亚基基因（Fly）和大鼠α-辅肌动蛋白基因，因为它们的主要转录物含有几个GCAUG拷贝。在转染实验中，Fox-1通过与调控外显子上游的GCAUG序列结合，诱导F1 γ基因的肌肉特异性外显子跳跃。Fox-1还调节α-辅肌动蛋白基因的互斥剪接，拮抗聚嘧啶片段结合蛋白（PTB）的抑制作用。据报道，GCAUG是必需的选择性剪接调控的几个基因，包括纤维连接蛋白。我们发现Fox-1促进了纤连蛋白EIIIB外显子的包含。因此，我们得出结论，Fox-1通过GCAUG在组织特异性剪接的正向和负向调节中起着关键作用。
Alternative splicing is one of the central mechanisms that regulate eukaryotic gene expression. Here we report a tissue-specific RNA-binding protein, Fox-1, which regulates alternative splicing in vertebrates. Fox-1 bound specifically to a pentanucleotide GCAUG in vitro. In zebrafish and mouse,fox-1 is expressed in heart and skeletal muscles. As candidates for muscle-specific targets of Fox-1, we considered two genes, the human mitochondrial ATP synthase gamma-subunit gene (Fly) and the rat alpha-actinin gene, because their primary transcripts contain several copies of GCAUG. In transfection experiments, Fox-1 induced muscle-specific exon skipping of the F1gamma gene via binding to GCAUG sequences upstream of the regulated exon. Fox-1 also regulated mutually exclusive splicing of the alpha-actinin gene, antagonizing the repressive effect of polypyrimidine tract-binding protein (PTB). It has been reported that GCAUG is essential for the alternative splicing regulation of several genes including fibronectin. We found that Fox-1 promoted inclusion of the fibronectin EIIIB exon. Thus, we conclude that Fox-1 plays key roles in both positive and negative regulation of tissue-specific splicing via GCAUG.