Zaretsky Joseph Z, Barnea Itay, Aylon Yael, Gorivodsky Marat, Wreschner Daniel H, Keydar Iafa
Department of Cell Research and Immunology, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel.
Mol Cancer. 2006 Nov 5;5:57. doi: 10.1186/1476-4598-5-57.
The MUC1 gene encodes a mucin glycoprotein(s) which is basally expressed in most epithelial cells. In breast adenocarcinoma and a variety of epithelial tumors its transcription is dramatically upregulated. Of particular relevance to breast cancer, steroid hormones also stimulate the expression of the MUC1 gene. The MUC1 gene directs expression of several protein isoforms, which participate in many crucial cell processes. Although the MUC1 gene plays a critical role in cell physiology and pathology, little is known about its promoter organization and transcriptional regulation. The goal of this study was to provide insight into the structure and transcriptional activity of the MUC1 promoter.
Using TRANSFAC and TSSG soft-ware programs the transcription factor binding sites of the MUC1 promoter were analyzed and a map of transcription cis-elements was constructed. The effect of different MUC1 promoter regions on MUC1 gene expression was monitored. Different regions of the MUC1 promoter were analyzed for their ability to control expression of specific MUC1 isoforms. Differences in the expression of human MUC1 gene transfected into mouse cells (heterologous artificial system) compared to human cells (homologous natural system) were observed. The role of estrogen on MUC1 isoform expression in human breast cancer cells, MCF-7 and T47D, was also analyzed. It was shown for the first time that synthesis of MUC1/SEC is dependent on estrogen whereas expression of MUC1/TM did not demonstrate such dependence. Moreover, the estrogen receptor alpha, ERalpha, could bind in vitro estrogen responsive cis-elements, EREs, that are present in the MUC1 promoter. The potential roles of different regions of the MUC1 promoter and ER in regulation of MUC1 gene expression are discussed.
Analysis of the structure and transcriptional activity of the MUC1 promoter performed in this study helps to better understand the mechanisms controlling transcription of the MUC1 gene. The role of different regions of the MUC1 promoter in expression of the MUC1 isoforms and possible function of ERalpha in this process has been established. The data obtained in this study may help in development of molecular modalities for controlled regulation of the MUC1 gene thus contributing to progress in breast cancer gene therapy.
MUC1基因编码一种粘蛋白糖蛋白，其在大多数上皮细胞中呈基础表达。在乳腺腺癌和多种上皮肿瘤中，其转录显著上调。与乳腺癌特别相关的是，类固醇激素也刺激MUC1基因的表达。MUC1基因指导几种蛋白质异构体的表达，这些异构体参与许多关键的细胞过程。尽管MUC1基因在细胞生理和病理中起关键作用，但其启动子组织和转录调控却知之甚少。本研究的目的是深入了解MUC1启动子的结构和转录活性。
使用TRANSFAC和TSSG软件程序分析了MUC1启动子的转录因子结合位点，并构建了转录顺式元件图谱。监测了不同MUC1启动子区域对MUC1基因表达的影响。分析了MUC1启动子的不同区域控制特定MUC1异构体表达的能力。观察到与人类细胞（同源天然系统）相比，转染到小鼠细胞（异源人工系统）中的人类MUC1基因表达的差异。还分析了雌激素对人乳腺癌细胞MCF-7和T47D中MUC1异构体表达的作用。首次表明MUC1/SEC的合成依赖于雌激素，而MUC1/TM的表达则未显示出这种依赖性。此外，雌激素受体α（ERα）可以在体外结合MUC1启动子中存在的雌激素反应性顺式元件（ERE）。讨论了MUC1启动子不同区域和ER在MUC1基因表达调控中的潜在作用。
本研究中对MUC1启动子结构和转录活性的分析有助于更好地理解控制MUC1基因转录的机制。已确定MUC1启动子不同区域在MUC1异构体表达中的作用以及ERα在此过程中的可能功能。本研究获得的数据可能有助于开发用于可控调节MUC1基因的分子方法，从而推动乳腺癌基因治疗的进展。
