L1CAM expression in endometrial carcinomas is regulated by usage of two different promoter regions.
L1CAM expression in endometrial carcinomas is regulated by usage of two different promoter regions.
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DOI：
10.1186/1471-2199-11-64
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发表时间：
2010-08-27
影响因子：
--
通讯作者：
Altevogt P
中科院分区：
文献类型：
--
作者：
Pfeifer M;Schirmer U;Geismann C;Schäfer H;Sebens S;Altevogt P
L1细胞黏附分子（L1CAM）最初被鉴定为一种参与轴突导向的神经黏附分子。在许多人类上皮癌中，L1CAM过度表达，从而增强细胞运动性、侵袭性和转移形成。L1CAM阳性的癌症与不良预后相关。近期数据指出，L1CAM的调控方式类似于上皮 - 间质转化（EMT）。先前的研究暗示转录因子Slug和/或β - 连环蛋白参与L1CAM的转录调控。然而，人类L1CAM在转录水平的表达调控尚未被充分理解。
为了更好地理解L1CAM转录调控的分子基础，我们对人类L1CAM启动子进行了详细的表征。我们确定了两个转录起始位点，第一个位于非翻译外显子0之前（启动子1），另一个紧邻第一个编码蛋白质的外显子1（启动子2）。这两个位点在子宫内膜癌（EC）细胞系中都得到了验证，并且似乎以细胞类型特异性的方式被使用。所确定的两个启动子区域在荧光素酶报告基因检测中显示出活性。染色质免疫沉淀分析证实了计算机预测的E - 盒（转录因子Snail和Slug的结合位点）以及Lef - 1位点（与β - 连环蛋白介导的转录调控相关）在两个启动子中都存在。β - 连环蛋白的过度表达仅增强启动子1的活性，而Slug增强启动子1和2的活性，这表明两个启动子都可以有活性。β - 连环蛋白或Slug的过度表达能够以细胞类型特异性的方式上调L1CAM的表达。
我们的研究结果首次提供了证据，表明L1CAM基因具有两个功能性的启动子位点，它们以细胞类型特异性的方式被使用。Slug和β - 连环蛋白参与L1CAM的转录调控。然而，在EC细胞系中，是Slug而非β - 连环蛋白的水平与L1CAM的表达相关。我们的发现表明，L1CAM的转录调控比预期的更为复杂，并且这项研究为更好地理解非神经/肿瘤细胞中L1CAM的调控提供了基础。
The L1 cell adhesion molecule (L1CAM) was originally identified as a neural adhesion molecule involved in axon guidance. In many human epithelial carcinomas L1CAM is overexpressed and thereby augments cell motility, invasion and metastasis formation. L1CAM positive carcinomas are associated with bad prognosis. Recent data point out that L1CAM is regulated in a fashion similar to epithelial-mesenchymal transition (EMT). Previous studies have implied the transcription factors Slug and/or β-catenin in L1CAM transcriptional regulation. However, the regulation of human L1CAM expression at the transcriptional level is not well understood. To better understand the molecular basis of L1CAM transcriptional regulation, we carried out a detailed characterization of the human L1CAM promoter. We identified two transcription start sites, the first in front of a non-translated exon 0 (promoter 1) and the other next to the first protein-coding exon 1 (promoter 2). Both sites could be verified in endometrial carcinoma (EC) cell lines and appear to be used in a cell-type specific manner. The two identified promoter regions showed activity in luciferase reporter assays. Chromatin-IP analyses confirmed the in silico predicted E-boxes, binding sites for transcription factors Snail and Slug, as well as Lef-1 sites, which are related to β-catenin-mediated transcriptional regulation, in both promoters. Overexpression of β-catenin exclusively augmented activity of promoter 1 whereas Slug enhanced promoter 1 and 2 activity suggesting that both promoters can be active. Overexpression of β-catenin or Slug could upregulate L1CAM expression in a cell-type specific manner. Our results, for the first time, provide evidence that the L1CAM gene has two functionally active promoter sites that are used in a cell-type specific manner. Slug and β-catenin are involved L1CAM transcriptional regulation. Nevertheless, Slug rather than β-catenin levels are correlated with L1CAM expression in EC cell lines. Our findings suggest that the L1CAM transcriptional regulation is more complex than anticipated and this study provides the basis for a better understanding of L1CAM regulation in non-neuronal/tumor cells.
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影响因子：
2.8
作者：
Brabletz, T;Jung, A;Kirchner, T
通讯作者：
Kirchner, T
影响因子：
7.5
作者：
Schachner, M
通讯作者：
Schachner, M
影响因子：
8
作者：
Muerkoester, S. Sebens;Werbing, V.;Schaefer, H.
通讯作者：
Schaefer, H.
影响因子：
4.7
作者：
Stoeck, Alexander;Gast, Daniela;Altevogt, Peter
通讯作者：
Altevogt, Peter
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4
作者：
Bolós, V;Peinado, H;Cano, A
通讯作者：
Cano, A