Ets gene PEA3 cooperates with β-catenin-Lef-1 and c-Jun in regulation of osteopontin transcription
Ets gene PEA3 cooperates with β-catenin-Lef-1 and c-Jun in regulation of osteopontin transcription
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DOI：
10.1074/jbc.m311131200
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发表时间：
2004-05-14
影响因子：
4.8
通讯作者：
Campbell, FC
中科院分区：
文献类型：
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作者：
El-Tanani, M;Platt-Higgins, A;Campbell, FC
骨桥蛋白（OPN）是一种多功能蛋白，与乳腺发育、肿瘤变化和转移有关。骨桥蛋白是β-连环蛋白-T细胞因子信号传导的靶基因，其在乳腺癌发生过程中通常受到干扰，但对骨桥蛋白调控的理解是不完整的。数据库辅助的OPN启动子区域的生物信息学分析揭示了T细胞因子、Ets和AP-1结合基序的存在。在这里，我们报告，β-连环蛋白，Lef-1，Ets转录因子，和AP-1蛋白c-Jun每个弱增强荧光素酶表达的OPN启动子荧光素酶报告构建体，瞬时转染到大鼠乳腺细胞系。然而，OPN启动子对β-连环蛋白和Lef-1的反应性被Ets转录因子包括Ets-1、Ets-2、ERM，特别是PEA 3显著增强。PEA 3还增强了启动子对AP-1蛋白c-Jun的反应性。将β-连环蛋白、Lef-1、PEA 3和c-Jun联合转染细胞可使荧光素酶表达增加280倍，并诱导内源性大鼠OPN的表达。在六个人乳腺细胞系中，那些高表达OPN的细胞也表达PEA 3和Ets-1。此外，在检测的29例人乳腺癌中，OPN免疫细胞化学染色与β-连环蛋白、Ets-1、Ets-2、PEA 3或c-Jun之一显著相关。这项研究表明，β-连环蛋白/ Lef-1，Ets和AP-1转录因子可以在大鼠乳腺细胞系中合作刺激OPN的转录，并且它们的独立存在与一组人类乳腺癌中的OPN相关。这些结果表明，这些转录因子在人乳腺癌中的存在部分地导致了OPN的过度表达，而OPN反过来又与乳腺肿瘤的进展和转移有关。
Osteopontin (OPN) is a multifunctional protein implicated in mammary development, neoplastic change, and metastasis. OPN is a target gene for beta-catenin-T cell factor signaling, which is commonly disturbed during mammary oncogenesis, but the understanding of OPN regulation is incomplete. Data base-assisted bioinformatic analysis of the OPN promoter region has revealed the presence of T cell factor-, Ets-, and AP-1-binding motifs. Here we report that beta-catenin, Lef-1, Ets transcription factors, and the AP-1 protein c-Jun each weakly enhanced luciferase expression from a OPN promoter-luciferase reporter construct, transiently transfected into a rat mammary cell line. OPN promoter responsiveness to beta-catenin and Lef-1, however, was considerably enhanced by Ets transcription factors including Ets-1, Ets-2, ERM, and particularly PEA3. PEA3 also enhanced promoter responsiveness to the AP-1 protein c-Jun. Co-transfection of cells with beta-catenin, Lef-1, PEA3, and c-Jun in combination increased luciferase expression by up to 280-fold and induced expression of endogenous rat OPN. In six human breast cell lines, those that highly expressed OPN also expressed PEA3 and Ets-1. Moreover, there was a significant association of immunocytochemical staining for OPN and one of beta-catenin, Ets-1, Ets-2, PEA3, or c-Jun, in the 29 human breast carcinomas tested. This study shows that beta-catenin/ Lef-1, Ets, and AP-1 transcription factors can cooperate in a rat mammary cell line in stimulating transcription of OPN and that their independent presence is associated with that of OPN in a group of human breast cancers. These results suggest that the presence of these transcription factors in human breast cancer is responsible in part for the overexpression of OPN that, in turn, is implicated in mammary neoplastic progression and metastasis.