Regulation of Ich-1 pre-mRNA alternative splicing and apoptosis by mammalian splicing factors
Regulation of Ich-1 pre-mRNA alternative splicing and apoptosis by mammalian splicing factors
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DOI：
10.1073/pnas.95.16.9155
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发表时间：
1998-08-04
影响因子：
11.1
通讯作者：
Wu, JY
中科院分区：
文献类型：
--
作者：
Jiang, ZH;Zhang, WJ;Wu, JY
选择性剪接在调节细胞凋亡中的重要性已经通过由参与细胞凋亡的几个基因的选择性剪接产生的功能拮抗蛋白的发现而被提出，其中，Ich-1 Ich-1（也称为半胱天冬酶-2）编码半胱天冬酶蛋白酶家族的一个成员。作为选择性剪接的结果，产生两种形式的Ich-1：Ich-1 L引起细胞凋亡，Ich-1 S阻止细胞凋亡。Ich-1选择性剪接的确切性质及其调控尚不清楚。在这里，我们表明，Ich-1 L和Ich-1 S转录本的产生是由一个61-bp外显子的选择性排除或包含引起的。富含丝氨酸-精氨酸的蛋白质SC 35和ASF/SF 2促进外显子跳跃，降低Ich-1 S与Ich-1 L转录本的比率;而异质核核糖核蛋白A1促进外显子包含，增加该比率。此外，在培养的细胞中，SC 35过表达增加细胞凋亡，而异质核核糖核蛋白A1过表达减少细胞凋亡。这些结果提供了第一个直接的证据，剪接因子可以调节Ich-1的选择性剪接，并建议选择性剪接可能是一个重要的调控机制，细胞凋亡。
The importance of alternative splicing in regulating apoptosis has been suggested by findings of functionally antagonistic proteins generated by alternative splicing of several genes involved in apoptosis, Among these, Ich-1 (also named as caspase-2) encodes a member of the caspase family of proteases, Two forms of Ich-1 are produced as a result of alternative splicing: Ich-1L, which causes apoptosis, and Ich-1S, which prevents apoptosis, The precise nature of Ich-1 alternative splicing and its regulation remain unknown. Here, we show that the production of Ich-1L land Ich-1S transcripts results from alternative exclusion or inclusion of a 61-bp exon, Several splicing factors can regulate Ich-1 splicing. Serine-arginine-rich proteins SC35 and ASF/SF2 promote exon skipping, decreasing the ratio of Ich-1S to Ich-1L transcripts; whereas heterogeneous nuclear ribonucleoprotein A1 facilitates exon inclusion, increasing this ratio. Furthermore, in cultured cells, SC35 overexpression increases apoptosis; whereas heterogeneous nuclear ribonucleoprotein A1 overexpression decreases apoptosis. These results provide the first direct evidence that splicing factors can regulate Ich-1 alternative splicing and suggest that alternative splicing may be an important regulatory mechanism for apoptosis.