Transcriptional regulation of human fibroblast growth factor receptor 1 by E2F-1
Transcriptional regulation of human fibroblast growth factor receptor 1 by E2F-1
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DOI：
10.1016/j.gene.2009.03.004
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发表时间：
2009-06-01
期刊：
影响因子：
3.5
通讯作者：
Imoto, Masaya
中科院分区：
文献类型：
--
作者：
Kanai, Mai;Tashiro, Etsu;Imoto, Masaya
成纤维细胞生长因子受体（FGFR）的过表达已在许多类型的人类肿瘤中观察到;然而，人类FGFR表达的调控机制在很大程度上仍是未知的。在本研究中，我们首先通过5 '-RACE技术确定了人FGFR 1基因的转录起始位点。此外，我们表明人FGFR 1的表达受E2 F-1的调节。人FGFR 1启动子的表征表明，相对于我们鉴定的人FGFR 1基因中的转录起始位点，在位置+4至+22和+25至+43处的两个非共有E2 F结合序列对于E2 F-1介导的人FGFR 1启动子的反式激活是关键的。这些位点的突变完全消除了人FGFR 1启动子对E2 F-1的反应以及电泳迁移率变化测定中的E2 F-1结合。此外，染色质免疫沉淀分析显示E2 F-1能够在体内结合人FGFR 1启动子。此外，人FGFR 1蛋白表达被E2 F-1的过表达上调，但被pRB的过表达原位下调，表明人FGFR 1的表达受pRB/E2 F通路调节。由于在肿瘤细胞中经常观察到pRB/E2 F通路的破坏，我们的研究结果为研究FGFR 1在肿瘤进展中的作用提供了有价值的信息。(c)2009爱思唯尔有限公司版权所有。
Overexpression of fibroblast growth factor receptors (FGFRs) has been observed in many types of human tumors; however, the regulatory mechanism of human FGFR expression is still largely unknown. In the present study, we first identified the transcriptional initiation site in the human FGFR 1 gene by 5'-RACE. Furthermore, we show that the expression of human FGFR 1 is regulated by E2F-1. Characterization of the human FGFR 1 promoter demonstrated that two non-consensus E2F binding sequences at positions +4 to +22 and +25 to +43 relative to our identified transcriptional initiation site in the human FGFR 1 gene were critical for E2F-1-mediated transactivation of human FGFR 1 promoter. Mutations of these sites completely abolished the response of human FGFR 1 promoter to E2F-1 as well as E2F-1 binding in electrophoretic mobility-shift assays. Furthermore, chromatin immunoprecipitation assay showed that E2F-1 was able to bind in vivo to the human FGFR 1 promoter. Moreover, human FGFR 1 protein expression was up-regulated by the overexpression of E2F-1, but down-regulated by the overexpression of pRB in situ, suggesting that the expression of human FGFR 1 is regulated by the pRB/E2F pathway. Because disruption of the pRB/E2F pathway is frequently observed in tumor cells, our findings provide valuable information for studying the role of FGFR 1 in tumor progression. (c) 2009 Elsevier B.V. All rights reserved.