A STAT-responsive element in the promoter of the episialin/MUC1 gene is involved in its overexpression in carcinoma cells
A STAT-responsive element in the promoter of the episialin/MUC1 gene is involved in its overexpression in carcinoma cells
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DOI：
10.1074/jbc.m009449200
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发表时间：
2001-03-02
影响因子：
4.8
通讯作者：
Hilkens, J
中科院分区：
文献类型：
--
作者：
Gaemers, IC;Vos, HL;Hilkens, J
许多人类癌症高度过量产生粘蛋白样糖蛋白表唾液酸蛋白 (MUC1)。我们之前已经在多种哺乳动物细胞系中证明，这种非常大的跨膜分子的过度表达会减少细胞粘附，这表明表唾液酸蛋白/MUC1过度表达可能在肿瘤侵袭和转移中发挥重要作用。通过使用原位杂交，我们在此表明，相对于邻近正常乳腺上皮中的表达，乳腺癌细胞中的表唾液酸蛋白/MUC1 mRNA表达可增加10倍以上。在寻找这种过度表达的分子机制时，我们观察到表唾液酸蛋白/MUC1启动子包含一个STAT家族转录因子的候选结合位点，类似于转录起始位点上游的500个碱基对。细胞因子和/或生长因子（例如白细胞介素 6 或干扰素 γ）可以激活 STAT。在人乳腺癌细胞系 T47D 中，两种化合物都能够在靠近转录起始位点的 750 个碱基对 MUC1 启动子片段的控制下刺激荧光素酶报告基因的转录。观察到的增加完全是由单个 STAT 结合位点介导的，因为该位点的突变消除了白细胞介素 6 和干扰素 γ 对报告基因的刺激。此外，STAT位点的突变还降低了未刺激的T47D细胞中的启动子活性，这表明STAT结合位点是参与肿瘤细胞中MUC1过度表达的元件之一。
The mucin-like glycoprotein episialin (MUC1) is highly overproduced by a number of human carcinomas. We have shown previously in a variety of mammalian cell lines that overexpression of this very large transmembrane molecule diminishes cellular adhesion, suggesting that episialin/MUC1 overexpression may play an important role in tumor invasion and metastasis. By using in situ hybridization, we show here that episialin/MUC1 mRNA expression can be increased more than 10-fold in breast carcinoma cells relative to the expression in adjacent normal breast epithelium. In search of the molecular mechanism of this overexpression, we observed that the episialin/MUC1 promoter contains a candidate binding site for transcription factors of the STAT family similar to 500 base pairs upstream of the transcription start site. Cytokines and/or growth factors such as interleukin-6 or interferon-gamma can activate STATs. In the human breast carcinoma cell line T47D, both compounds are able to stimulate transcription of a luciferase reporter gene under the control of a 750-base pair MUC1 promoter fragment proximal to the transcription start site. The observed increase is entirely mediated by the single STAT-binding site, since mutation of this site abolishes stimulation of the reporter by interleukin-6 and interferon-gamma. In addition, mutation of the STAT site also decreased the promoter activity in nonstimulated T47D cells, suggesting that the STAT-binding site is among the elements that are involved in the overexpression of MUC1 in tumor cells.