Antagonistic roles of four SR proteins in the biosynthesis of alternatively spliced tissue factor transcripts in monocytic cells
Antagonistic roles of four SR proteins in the biosynthesis of alternatively spliced tissue factor transcripts in monocytic cells
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DOI：
10.1189/jlb.0409252
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发表时间：
2010-01-01
影响因子：
5.5
通讯作者：
Bogdanov, Vladimir Y.
中科院分区：
文献类型：
--
作者：
Chandradas, Sajiv;Deikus, Gintaras;Bogdanov, Vladimir Y.
在募集到实体组织后，外周血单核细胞表达许多促炎分子，包括TF，其是凝血的触发物，也促进细胞-细胞相互作用和组织重塑。单核细胞表达两种形式的TF：flTF，一种高度凝血的跨膜形式，和asTF，一种高度促血管生成的可溶性TF形式。两种TF形式的生物合成通过前体mRNA剪接期间外显子5的选择性加工发生。其包含导致flTF mRNA和其排除导致asTF mRNA。我们最近开发了一个剪接报告系统，并确定了两个剪接体成分，SR蛋白ASF/SF 2和SRp 55，在外显子5包含中起着关键作用。在这份报告中，我们首次表明，在人类单核细胞中表达的其他两个SR蛋白，SRp 40和SC 35，拮抗ASF/SF 2和SRp 55通过竞争结合到外显子5中的某些位点，从而促进TF外显子5排除，一个独特的asTF生物合成的事件。我们还表明，TF外显子5前的内含子具有U2内含子中很少发现的特征。我们的研究结果表明，TF前mRNA剪接的调节可以通过SR蛋白活性的修饰来完成，从而促进了调节单核细胞/巨噬细胞“TF谱”的新治疗策略的开发。J. Leukoc. 87：147-152; 2010.
Following recruitment to solid tissues, peripheral blood monocytes express a number of proinflammatory molecules including TF, a trigger of coagulation that also promotes cell-cell interactions and tissue remodeling. Monocytes express two forms of TF: flTF, a highly coagulant transmembrane form, and asTF, a highly proangiogenic, soluble TF form. Biosynthesis of the two TF forms occurs via alternative processing of exon 5 during pre-mRNA splicing. Its inclusion results in flTF mRNA and its exclusion, asTF mRNA. We developed a splicing reporter system recently and determined that two spliceosomal constituents, SR proteins ASF/SF2 and SRp55, play a pivotal role in exon 5 inclusion. In this report, we show for the first time that two other SR proteins expressed in human monocytes, SRp40 and SC35, antagonize ASF/SF2 and SRp55 by competing for binding to certain sites in exon 5, thereby promoting TF exon 5 exclusion, an event unique to asTF biosynthesis. We also show that the intron preceding TF exon 5 possesses characteristics rarely found in U2 introns. Our findings indicate that modulation of TF pre-mRNA splicing can be accomplished via modification of SR proteins' activity, facilitating development of novel therapeutic strategies to modulate the "TF profile" of monocytes/macrophages. J. Leukoc. Biol. 87: 147-152; 2010.