Iwai Akio, Marusawa Hiroyuki, Matsuzawa Shu-ichi, Fukushima Toru, Hijikata Makoto, Reed John C, Shimotohno Kunitada, Chiba Tsutomu
Division of Gastroenterology and Hepatology, Department of Medicine, Kyoto University, Japan.
Oncogene. 2004 Sep 30;23(45):7593-600. doi: 10.1038/sj.onc.1208016.
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.
β-连环蛋白是一种强大的致癌蛋白，其在癌细胞中的细胞质积累是常见现象。β-连环蛋白的水平受两种机制调节：腺瘤性息肉病大肠杆菌/Axin/糖原合酶激酶3β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。在本研究中，我们研究了p53诱导的人Siah家族蛋白表达在调节β-连环蛋白活性中的功能意义。我们通过逆转录聚合酶链反应表明，人Siah-1基因座产生了两种mRNA转录本，分别命名为人Siah-1和Siah-1L。有趣的是，Siah-1L的表达受p53上调，而人Siah-1的表达保持恒定。此外，在缺乏内源性p53的癌细胞中，引入外源性Siah-1L蛋白可下调β-连环蛋白蛋白，并促进抗癌药物诱导的细胞凋亡。因此，Siah-1L代表了人Siah家族的一个新成员，它在响应p53时被诱导，并在调节肿瘤细胞中β-连环蛋白活性方面发挥重要作用。这些发现还提示了恢复在p53失活的癌细胞中丢失的肿瘤抑制途径的新策略。
