Subcellular localization of ATBF1 regulates MUC5AC transcription in gastric cancer
Subcellular localization of ATBF1 regulates MUC5AC transcription in gastric cancer
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DOI：
10.1002/ijc.22654
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发表时间：
2007-07-15
影响因子：
6.4
通讯作者：
Joh, Takashi
中科院分区：
文献类型：
--
作者：
Mori, Yoshinori;Kataoka, Hiromi;Joh, Takashi
人类胃上皮具有独特的粘蛋白基因表达模式，该模式在胃肠道疾病中发生显着改变。这种粘蛋白表达的改变，包括粘蛋白MUC5AC，可能与胃癌的发生和预后有关，有报道MUC5AC阳性的胃癌预后不良。然而，MUC5AC转录调控的分子机制尚未完全阐明。 AT 基序结合因子 1 (ATBF1) 是一种同源转录调节因子，最近被鉴定为肿瘤抑制基因，其亚细胞定位表明与细胞增殖和分化有关。我们研究了 ATBF1 对 MUC5AC 转录调控的机制。免疫组织化学测定，在 123 个胃癌病灶中，细胞核中表达的 ATBF1 显着抑制 MUC5AC 的表达。此外，对 MUC5AC 启动子区域的分析揭示了一个 AT 基序样元件。如双荧光素酶报告基因测定所示，该元件被发现对于 ATBF1 抑制 MUC5AC 启动子活性至关重要。过表达的 ATBF1 还显着抑制胃癌细胞中的内源 MUC5AC 蛋白表达。染色质免疫沉淀表明 ATBF1 与 MUC5AC 启动子中的 AT 基序样元件结合。这些结果表明，细胞核中的 ATBF1 通过与 MUC5AC 启动子中的 AT 基序样元件结合，负向调节胃癌中的 MUC5AC 基因。 (c) 2007 年 Wiley-Liss, Inc.
Human gastric epithelium has a unique mucin gene expression pattern, which becomes markedly altered in gastrointestinal disorder. This alteration in mucin expression, including the mucin MUC5AC, may be related to the development and prognosis of gastric cancers, and MUC5AC-positive gastric cancer has been reported to be poor prognosis. However, the molecular mechanism of MUC5AC transcriptional regulation has not been fully elucidated. AT motif-binding factor 1 (ATBF1) is a homeotic transcriptional regulatory factor recently identified as a tumor suppressor gene, and its subcellular localization suggests a link to cell proliferation and differentiation. We investigated the mechanism of MUC5AC transcriptional regulation by ATBF1. In 123 gastric cancer lesions, ATBF1 expressed in the nucleus significantly suppressed MUC5AC expression, as determined by immunohistochemistry. In addition, analysis of the MUC5AC promoter region revealed an AT motif-like element. This element was found to be essential for ATBF1 suppression of MUC5AC promoter activity as shown in a dual luciferase-reporter assay. Over-expressed ATBF1 also significantly suppressed enclogenous MUC5AC protein expression in gastric cancer cells. Chromatin immunoprecipitation demonstrated that ATBF1 binds to the AT motif-like element in the MUC5AC promoter. These results indicate that ATBF1 in the nucleus negatively regulates the MUC5AC gene in gastric cancer by binding to an AT motif-like element in the MUC5AC promoter. (c) 2007 Wiley-Liss, Inc.