Fascin-1 promoter activity is regulated by CREB and the aryl hydrocarbon receptor in human carcinoma cells.
Fascin-1 promoter activity is regulated by CREB and the aryl hydrocarbon receptor in human carcinoma cells.
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DOI：
10.1371/journal.pone.0005130
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Adams JC
中科院分区：
文献类型：
--
作者：
Hashimoto Y;Loftis DW;Adams JC
肌成束蛋白是一种肌动蛋白捆绑蛋白，其在大多数正常上皮中不存在，但在多种形式的人类癌中上调，其中其表达在临床上与不良预后相关。fascin-1转录在癌细胞中是如何被激活的在很大程度上是未知的，尽管β-catenin信号调节的假说已经受到关注。这个问题很重要，因为成束蛋白在人类癌症中的表达具有临床意义。通过比较基因组学，我们从六种哺乳动物的fascin-1启动子区的DNA序列进行了无偏分析。我们确定了两个高度保守的基序集中的区域。在fascin阳性和阴性人乳腺癌和结肠癌细胞中，以及在组成型fascin阳性的人真皮成纤维细胞中进行人fascin-1启动子的荧光素酶启动子报告基因测定。在所有fascin阳性细胞中，包含多个高度保守基序的-219/+114区域具有强转录活性。-2953/-1582区域似乎含有阻遏物活性。通过研究-219/+114区域内保守基序的单个或多个点突变对转录报告活性的影响，我们首次确定了保守的CREB和AhR结合基序是人类结肠癌细胞中转录活性的主要决定因素。来自fascin阳性或阴性人结肠癌细胞提取物的CREB、AhR或β-连环蛋白的染色质免疫沉淀鉴定出CREB和AhR特异性地与fascin阳性结肠癌细胞中FSCN 1启动子的−219/+114区域相关联。β-连环蛋白的结合对fascin阳性细胞不是特异性的。侵袭性人类癌中肌成束蛋白-1的上调似乎具有多因素基础。这些数据确定了CREB和AhR作为人癌细胞中FSCN-1转录的主要特异性调节因子的新作用，但不支持β-连环蛋白信号传导具有核心作用的假设。
Fascin is an actin-bundling protein that is absent from most normal epithelia yet is upregulated in multiple forms of human carcinoma, where its expression correlates clinically with a poor prognosis. How fascin-1 transcription is activated in carcinoma cells is largely unknown, although the hypothesis of regulation by β-catenin signaling has received attention. The question is important because of the clinical significance of fascin expression in human carcinomas. Through comparative genomics we made an unbiased analysis of the DNA sequence of the fascin-1 promoter region from six mammalian species. We identified two regions in which highly conserved motifs are concentrated. Luciferase promoter reporter assays for the human fascin-1 promoter were carried out in fascin-positive and -negative human breast and colon carcinoma cells, and in human dermal fibroblasts that are constitutively fascin-positive. In all fascin-positive cells, the region −219/+114 that contains multiple highly conserved motifs had strong transcriptional activity. The region −2953/−1582 appeared to contain repressor activity. By examining the effects of single or multiple point mutations of conserved motifs within the −219/+114 region on transcriptional reporter activity, we identified for the first time that the conserved CREB and AhR binding motifs are major determinants of transcriptional activity in human colon carcinoma cells. Chromatin immunoprecipitations for CREB, AhR or β-catenin from extracts from fascin-positive or -negative human colon carcinoma cells identified that CREB and AhR specifically associate with the −219/+114 region of the FSCN1 promoter in fascin-positive colon carcinoma cells. An association of β-catenin was not specific to fascin-positive cells. Upregulation of fascin-1 in aggressive human carcinomas appears to have a multi-factorial basis. The data identify novel roles for CREB and AhR as major, specific regulators of FSCN-1 transcription in human carcinoma cells but do not support the hypothesis that β-catenin signaling has a central role.
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影响因子：
3.3
作者：
Hashimoto, Yosuke;Parsons, Maddy;Adams, Josephine C.
通讯作者：
Adams, Josephine C.
影响因子：
4.4
作者：
Bros, M;Ross, XL;Ross, R
通讯作者：
Ross, R
影响因子：
14.9
作者：
Blanchette, M;Tompa, M
通讯作者：
Tompa, M
影响因子：
3.8
作者：
Hashimoto Y;Skacel M;Lavery IC;Mukherjee AL;Casey G;Adams JC
通讯作者：
Adams JC
影响因子：
56.9
作者：
Gibbs, Richard A.;Rogers, Jeffrey;Zwieg, Ann S.
通讯作者：
Zwieg, Ann S.