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首页> 外文期刊>Molecular and Cellular Biology >The RNA-Binding Protein TIA-1 Is a Novel Mammalian Splicing Regulator Acting through Intron Sequences Adjacent to a 5′ Splice Site
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The RNA-Binding Protein TIA-1 Is a Novel Mammalian Splicing Regulator Acting through Intron Sequences Adjacent to a 5′ Splice Site

机译：RNA结合蛋白TIA-1是一种新型的哺乳动物剪接调节剂，通过与5'剪接位点相邻的内含子序列起作用

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Splicing of the K-SAM alternative exon of the fibroblast growth factor receptor 2 gene is heavily dependent on the U-rich sequence IAS1 lying immediately downstream from its 5′ splice site. We show that IAS1 can activate the use of several heterologous 5′ splice sites in vitro. Addition of the RNA-binding protein TIA-1 to splicing extracts preferentially enhances the use of 5′ splice sites linked to IAS1. TIA-1 can provoke a switch to use of such sites on pre-mRNAs with competing 5′ splice sites, only one of which is adjacent to IAS1. Using a combination of UV cross-linking and specific immunoprecipitation steps, we show that TIA-1 binds to IAS1 in cell extracts. This binding is stronger if IAS1 is adjacent to a 5′ splice site and is U1 snRNP dependent. Overexpression of TIA-1 in cultured cells activates K-SAM exon splicing in an IAS1-dependent manner. If IAS1 is replaced with a bacteriophage MS2 operator, splicing of the K-SAM exon can no longer be activated by TIA-1. Splicing can, however, be activated by a TIA-1–MS2 coat protein fusion, provided that the operator is close to the 5′ splice site. Our results identify TIA-1 as a novel splicing regulator, which acts by binding to intron sequences immediately downstream from a 5′ splice site in a U1 snRNP-dependent fashion. TIA-1 is distantly related to the yeast U1 snRNP protein Nam8p, and the functional similarities between the two proteins are discussed.
机译：成纤维细胞生长因子受体2基因的K-SAM替代外显子的剪接很大程度上取决于位于5'剪接位点下游的富U序列IAS1。我们显示，IAS1可以在体外激活几个异源5'剪接位点的使用。将RNA结合蛋白TIA-1加入剪接提取物中可优先提高与IAS1相连的5'剪接位点的使用。 TIA-1可以引发在具有竞争性5'剪接位点的前mRNA上使用此类位点的转换，其中只有一个与IAS1相邻。使用UV交联和特定的免疫沉淀步骤的组合，我们显示TIA-1绑定到IAS1在细胞提取物中。如果IAS1与5'剪接位点相邻并且是U1 snRNP依赖性的，则这种结合会更强。 TIA-1在培养细胞中的过表达以IAS1依赖性方式激活K-SAM外显子剪接。如果将IAS1替换为噬菌体MS2操作员，则TIA-1无法再激活K-SAM外显子的剪接。但是，只要操作员靠近5'剪接位点，TIA-1–MS2外壳蛋白融合蛋白即可激活剪接。我们的研究结果确定TIA-1是一种新型的剪接调节剂，其通过以U1 snRNP依赖性方式与5'剪接位点下游的内含子序列结合而起作用。 TIA-1与酵母U1 snRNP蛋白Nam8p密切相关，并讨论了这两种蛋白之间的功能相似性。

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