Siah-1S, a novel splice variant of Siah-1 (seven in absentia homolog), counteracts Siah-1-mediated downregulation of β-catenin
Siah-1S, a novel splice variant of Siah-1 (seven in absentia homolog), counteracts Siah-1-mediated downregulation of β-catenin
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DOI：
10.1038/sj.onc.1210449
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发表时间：
2007-09-20
期刊：
影响因子：
8
通讯作者：
Wu, M.
中科院分区：
文献类型：
--
作者：
Mei, Y.;Xie, C.;Wu, M.
已知Siah-1(7个缺席同源物)通过与Siah相互作用蛋白(SIP)、Skp1和EBI形成复合体而间接降解β-连环蛋白。在这里，我们报告了一种新的人类Siah-1剪接变体的特征，命名为Siah-1S，它是通过另一种剪接机制产生的。用于产生Siah-1的新的内含子/外显子连接遵循非传统的CT-AC规则。Siah-1的半衰期甚至比Siah-1更短，并且能够催化自身泛素化，从而导致其随后被蛋白酶体降解。SIAH-1S上调β-连环素依赖的Tcf/Lef转录激活，并拮抗SIAH-1‘S对依托泊苷诱导的MCF-7细胞凋亡的增强作用。此外，还发现Siah-1与Siah-1相互作用形成异二聚体或与自身形成同源二聚体。与同源二聚体Siah-1*Siah-1不同，Siah-1*Siah-1S和Siah-1S*Siah-1S都不能与Siah-1相互作用蛋白结合，这可能解释了Siah-1S对Siah-1的显性负效应的潜在机制。重要的是，体外软琼脂实验结果表明，Siah-1S具有促进细胞致瘤性的作用。
Siah-1 ( seven in absentia homolog) is known to cause indirect degradation of beta-catenin through formation of a complex with Siah-interacting protein ( SIP), Skp1 and Ebi. Here, we report the characterization of a novel splice variant of human Siah-1, designated Siah-1S, which is produced by an alternative splicing mechanism. The novel intron/exon junctions used to generate Siah-1S follow a non-conventional CT-AC rule. Siah-1S exhibits an even shorter half-life than Siah-1 and is able to catalyse self-ubiquitination that results in its subsequent degradation by proteasome. Siah-1S is shown to upregulate beta-catenin-dependent Tcf/Lef transcriptional activation and antagonize Siah-1's potentiation effect on the apoptosis induced by etoposide in MCF-7 cells. Additionally, Siah-1S is found to interact with Siah-1 to form heterodimer or with itself to form homodimer. Unlike homodimer Siah-1*Siah-1, neither Siah-1*Siah-1S nor Siah-1S*Siah-1S is able to bind to Siah-1-interacting protein, which may explain the underlying mechanism for Siah-1S's dominant negative effect on Siah-1. Importantly, results from in vitro soft agar assay demonstrated that Siah-1S displays a promotion effect on cells tumorigenicity.