Heterogeneous ribonucleoprotein M is a splicing regulatory protein that can enhance or silence splicing of alternatively spliced Exons
Heterogeneous ribonucleoprotein M is a splicing regulatory protein that can enhance or silence splicing of alternatively spliced Exons
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DOI：
10.1074/jbc.m704188200
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发表时间：
2007-12-14
影响因子：
4.8
通讯作者：
Carstens, Russ P.
中科院分区：
文献类型：
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作者：
Hovhannisyan, Ruben H.;Carstens, Russ P.
成纤维细胞生长因子受体2(FGFR2)选择性外显子IIIb和IIIc的剪接受辅助RNA顺式元件ISE/ISS-3的调控，该辅助RNA顺式元件促进外显子IIIb的剪接和外显子IIIc的沉默。利用RNA亲和层析，我们鉴定了异质性核核糖核蛋白M(HnRNP M)是一种剪接调节因子，以序列特异性的方式与ISE/ISS-3结合。HnRNP M的过表达促进了正常包括hnRNP M的细胞系中外显子IIIc的跳跃，而hnRNP M与ISE/ISS-3的结合被证明有助于这种剪接调节功能。因此，hnRNP M与hnRNP RNA结合蛋白家族的其他成员一起，在FGFR2选择性剪接的调控中发挥着组合作用。我们还确定hnRNP M可以影响其他几个选择性剪接外显子的剪接。HnRNP M的这种活性不仅包括诱导外显子跳跃的能力，还包括促进外显子包涵体的能力。这是第一个证明这个丰富的hnRNP家族成员在哺乳动物选择性剪接中的作用的报告，并表明该蛋白可能广泛地有助于剪接位点识别和选择性剪接调控的保真度。
Splicing of fibroblast growth factor receptor 2 (FGFR2) alternative exons IIIb and IIIc is regulated by the auxiliary RNA cis-element ISE/ISS-3 that promotes splicing of exons IIIb and silencing of exon IIIc. Using RNA affinity chromatography, we have identified heterogeneous nuclear ribonucleoprotein M (hnRNP M) as a splicing regulatory factor that binds to ISE/ISS-3 in a sequence-specific manner. Overexpression of hnRNP M promoted exon IIIc skipping in a cell line that normally includes it, and association of hnRNP M with ISE/ISS-3 was shown to contribute to this splicing regulatory function. Thus hnRNP M, along with other members of the hnRNP family of RNA-binding proteins, plays a combinatorial role in regulation of FGFR2 alternative splicing. We also determined that hnRNP M can affect the splicing of several other alternatively spliced exons. This activity of hnRNP M included the ability not only to induce exon skipping but also to promote exon inclusion. This is the first report demonstrating a role for this abundant hnRNP family member in alternative splicing in mammals and suggests that this protein may broadly contribute to the fidelity of splice site recognition and alternative splicing regulation.