Estrogen-induced proliferation of normal endometrial glandular cells is initiated by transcriptional activation of cyclin D1 via binding of c-Jun to an AP-1 sequence
Estrogen-induced proliferation of normal endometrial glandular cells is initiated by transcriptional activation of cyclin D1 via binding of c-Jun to an AP-1 sequence
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DOI：
10.1038/sj.onc.1207849
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发表时间：
2004-11-11
期刊：
影响因子：
8
通讯作者：
Konishi, I
中科院分区：
文献类型：
--
作者：
Shiozawa, T;Miyamoto, T;Konishi, I
为探讨雌激素诱导正常子宫内膜生长的机制，采用体外培养的正常子宫内膜腺细胞，分析了cyclin D1基因的反式激活系统。雌二醇（E2）处理培养的正常子宫内膜腺细胞诱导c-Jun上调，然后是cyclin D1蛋白，随后是cyclin E、A和B1蛋白的系列表达。E2处理后，细胞周期蛋白D1 mRNA表达的增加先于细胞周期蛋白D1蛋白表达的增加。荧光素酶分析使用删除构建的细胞周期蛋白D1启动子表明，E2诱导的转录活性的增加，观察到在记者含有AP-1结合位点序列，并在E2的情况下，c-Jun的共转染也表现出增加的转录活性，在相同的记者与AP-1序列。凝胶迁移试验使用E2处理的子宫内膜腺细胞和AP-1序列的细胞周期蛋白D1启动子的核提取物表明c-Jun蛋白和启动子之间的特异性结合。c-jun反义寡核苷酸转染腺细胞导致抑制E2诱导的cyclin D1 mRNA和蛋白的上调。这些发现表明，E2诱导的正常子宫内膜腺细胞增殖是通过c-Jun与AP-1序列结合，通过细胞周期蛋白D1的转录激活启动的。
To explore the mechanism of estrogen-induced growth of normal endometrium, the transactivation system of the cyclin D1 gene was analysed using cultured normal endometrial glandular cells. Estradiol (E2) treatment of cultured normal endometrial glandular cells induced upregulation of c-Jun, and then cyclin D1 proteins, followed by serial expressions of cyclins E, A and B1 proteins. Increase in the mRNA expression of cyclin D1 preceded the protein expression of cyclin D1 under E2 treatment. A luciferase assay using deletion constructs of the cyclin D1 promoter indicated that E2-induced increase in transcriptional activity was observed in reporters containing AP-1-binding site sequence, and that in the absence of E2, cotransfection of c-Jun also showed increase of transcriptional activity in the same reporters with AP-1 sequence. A gel shift assay using nuclear extract from E2-treated endometrial glandular cells and AP-1 sequences of the cyclin D1 promoter indicated specific binding between c-Jun protein and the promoter. Transfection of c-jun antisense oligonucleotides to the glandular cells resulted in the suppression of the E2-induced upregulation of cyclin D1 mRNA and protein. These findings suggest that E2-induced proliferation of normal endometrial glandular cells is initiated by transcriptional activation of cyclin D1 via binding of c-Jun to the AP-1 sequences.