Siah-1L, a novel transcript variant belonging to the human Siah family of proteins, regulates β-catenin activity in a p53-dependent manner
Siah-1L, a novel transcript variant belonging to the human Siah family of proteins, regulates β-catenin activity in a p53-dependent manner
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DOI：
10.1038/sj.onc.1208016
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发表时间：
2004-09-30
期刊：
影响因子：
8
通讯作者：
Chiba, T
中科院分区：
文献类型：
--
作者：
Iwai, A;Marusawa, H;Chiba, T
β-连环蛋白是一种有效的致癌蛋白，其细胞质积累是癌细胞中的常见事件。β-连环蛋白的水平受两种机制调节：腺瘤性结肠息肉病/Axin/糖原合成酶激酶3 β依赖性降解途径和Siah-1/ Siah相互作用蛋白/Ebi介导的降解途径。在这项研究中，我们研究了p53诱导的人Siah家族蛋白表达在β-连环蛋白活性调节中的功能意义。我们在这里显示，通过逆转录聚合酶链反应，两个mRNA转录，指定的人Siah-1和Siah-1 L，从人Siah-1基因座产生。有趣的是，Siah-1 L的表达被p53上调，而人Siah-1的表达是恒定的。此外，外源性Siah-1 L蛋白的引入下调了β-连环蛋白，并促进了缺乏内源性p53的癌细胞中由抗癌药物诱导的凋亡。因此，Siah-1 L代表人Siah家族的新成员，其响应于p53而被诱导，并且在肿瘤细胞中β-连环蛋白活性的调节中起重要作用。这些发现还提出了恢复p53失活的癌细胞中丢失的肿瘤抑制途径的新策略。
beta-Catenin is a potent oncogenic protein whose cytoplasmic accumulation is a frequent event in cancer cells. The level of beta-catenin is regulated by two mechanisms: the adenomatous polyposis coli/Axin/glycogen synthase kinase 3beta-dependent degradation pathway and the Siah-1/ Siah interacting protein/Ebi-mediated degradation pathway. In this study, we have investigated the functional significance of p53-inducible human Siah-family protein expression in the regulation of beta-catenin activity. We show here by reverse-transcriptase polymerase chain reaction that two mRNA transcripts, designated human Siah-1 and Siah-1L, are generated from the human Siah-1 locus. Interestingly, the expression of Siah-1L was upregulated by p53, whereas human Siah-1 expression was constant. Furthermore, introduction of exogenous Siah-1L protein downregulated beta-catenin protein and promoted apoptosis induced by anticancer drugs in cancer cells that lack endogenous p53. Thus, Siah-1L represents a new member of the human Siah family that is induced in response to p53 and plays an important role in the regulation of beta-catenin activity in tumor cells. These findings also suggest new strategies for restoring tumor suppressive pathways lost in cancer cells that have suffered p53 inactivation.