Inhibition of cyclin D1 expression by androgen receptor in breast cancer cells--identification of a novel androgen response element.
Inhibition of cyclin D1 expression by androgen receptor in breast cancer cells--identification of a novel androgen response element.
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DOI：
10.1093/nar/gkq278
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发表时间：
2010-09
影响因子：
14.9
通讯作者：
Andò S
中科院分区：
文献类型：
--
作者：
Lanzino M;Sisci D;Morelli C;Garofalo C;Catalano S;Casaburi I;Capparelli C;Giordano C;Giordano F;Maggiolini M;Andò S
细胞周期蛋白D1基因（CCND 1）是一个重要的丝裂原调控的细胞周期调控元件，其转录调控在乳腺癌的生长和发展中起着至关重要的作用。在这里，我们证明了非芳香化雄激素5-α-二氢睾酮（DHT）抑制内源性细胞周期蛋白D1的表达，证明了细胞周期蛋白D1的mRNA和蛋白水平的降低，CCND 1启动子活性的降低，在MCF-7细胞。CCND 1基因活性的DHT依赖性抑制需要雄激素受体（AR）DNA结合结构域的参与和完整性。定点诱变、DNA亲和沉淀试验、电泳迁移率变动试验和染色质免疫沉淀分析表明，这种抑制作用是配体依赖性的，它是通过AR与位于转录起始位点上游−570至−556 bp的雄激素反应元件（CCND 1-ARE）直接结合介导的，位于细胞周期蛋白D1近端启动子中。此外，AR介导的CCND 1的抑制涉及募集非典型孤儿核受体DAX 1作为多蛋白阻遏物复合物的组分，也包括组蛋白脱乙酰酶1的参与。总之，CCND 1-ARE的鉴定允许将细胞周期蛋白D1定义为乳腺中的特异性雄激素靶基因，并可能有助于解释雄激素对乳腺癌细胞增殖抑制作用的分子基础。
Cyclin D1 gene (CCND1) is a critical mitogen-regulated cell-cycle control element whose transcriptional modulation plays a crucial role in breast cancer growth and progression. Here we demonstrate that the non-aromatizable androgen 5-α-dihydrotestosterone (DHT) inhibits endogenous cyclin D1 expression, as evidenced by reduction of cyclin D1 mRNA and protein levels, and decrease of CCND1-promoter activity, in MCF-7 cells. The DHT-dependent inhibition of CCND1 gene activity requires the involvement and the integrity of the androgen receptor (AR) DNA-binding domain. Site directed mutagenesis, DNA affinity precipitation assay, electrophoretic mobility shift assay and chromatin immunoprecipitation analyses indicate that this inhibitory effect is ligand dependent and it is mediated by direct binding of AR to an androgen response element (CCND1-ARE) located at −570 to −556-bp upstream of the transcription start site, in the cyclin D1 proximal promoter. Moreover, AR-mediated repression of the CCND1 involves the recruitment of the atypical orphan nuclear receptor DAX1 as a component of a multiprotein repressor complex also embracing the participation of Histone Deacetylase 1. In conclusion, identification of the CCND1-ARE allows defining cyclin D1 as a specific androgen target gene in breast and might contribute to explain the molecular basis of the inhibitory role of androgens on breast cancer cells proliferation.
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影响因子：
4.8
作者：
Dupont, J;Karas, M;LeRoith, D
通讯作者：
LeRoith, D
影响因子：
3.5
作者：
Greeve, MA;Allan, FK;Bentel, JM
通讯作者：
Bentel, JM
影响因子：
2.5
作者：
Birrell, SN;Hall, RE;Tilley, WD
通讯作者：
Tilley, WD
影响因子：
5.6
作者：
Catalano, Stefania;Giordano, Cinzia;Ando, Sebastiano
通讯作者：
Ando, Sebastiano
DOI：
10.1038/nrg2485
发表时间：
2009-01
期刊：
Nature reviews. Genetics
影响因子：
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作者：
通讯作者：
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