Plakoglobin interacts with the transcription factor p53 and regulates the expression of 14-3-3σ
Plakoglobin interacts with the transcription factor p53 and regulates the expression of 14-3-3σ
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DOI：
10.1242/jcs.120642
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发表时间：
2013-07-15
影响因子：
4
通讯作者：
Pasdar, Manijeh
中科院分区：
文献类型：
--
作者：
Aktary, Zackie;Kulak, Stephen;Pasdar, Manijeh
血小板红蛋白（c-连环蛋白）是粘附体连接和桥粒的组成成分，具有信号传导能力，通常与肿瘤/转移抑制有关，其机制尚不明确。为了确定血小板红蛋白在肿瘤发生和转移中的作用，我们在人舌鳞癌（SCC9）细胞中表达血小板红蛋白，并比较亲代SCC9细胞及其表达血小板红蛋白的转染物（SCC9- pg）的mRNA谱。我们检测到几个p53靶基因的水平随着血小板红蛋白的表达而改变。在本研究中，我们确定了p53调控的肿瘤抑制因子14-3-3 sigma作为plakogloin -p53的直接靶基因。共免疫沉淀实验显示，血小板红蛋白和p53相互作用，染色质免疫沉淀和电泳迁移转移实验显示，血小板红蛋白和p53与14-3-3 α启动子相关。此外，荧光素酶报告基因检测显示，p53的转录活性在血小板红蛋白存在时增加。最后，在MCF-7细胞中敲除血小板红蛋白，然后进行荧光素酶测定，证实p53的转录活性在血小板红蛋白存在时增强。我们的数据表明，血小板红蛋白与p53一起调节基因表达，血小板红蛋白可能调节p53的转录活性，这可能部分解释了血小板红蛋白抑制肿瘤/转移的活性。
Plakoglobin (c-catenin), a constituent of the adherens junction and desmosomes, has signaling capabilities typically associated with tumor/metastasis suppression through mechanisms that remain undefined. To determine the role of plakoglobin during tumorigenesis and metastasis, we expressed plakoglobin in human tongue squamous cell carcinoma (SCC9) cells and compared the mRNA profiles of parental SCC9 cells and their plakoglobin-expressing transfectants (SCC9-PG). We detected several p53-target genes whose levels were altered upon plakoglobin expression. In this study, we identified the p53 regulated tumor suppressor 14-3-3 sigma as a direct plakoglobin-p53 target gene. Coimmunoprecipitation experiments revealed that plakoglobin and p53 interact, and chromatin immunoprecipitation and electrophoretic mobility shift assays revealed that plakoglobin and p53 associate with the 14-3-3 alpha promoter. Furthermore, luciferase reporter assays showed that p53 transcriptional activity is increased in the presence of plakoglobin. Finally, knockdown of plakoglobin in MCF-7 cells followed by luciferase assays confirmed that p53 transcriptional activity is enhanced in the presence of plakoglobin. Our data suggest that plakoglobin regulates gene expression in conjunction with p53 and that plakoglobin may regulate p53 transcriptional activity, which may account, in part, for the tumor/metastasis suppressor activity of plakoglobin.