Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells.
Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells.
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DOI：
10.1038/cddis.2014.497
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发表时间：
2014-12-04
影响因子：
9
通讯作者：
Migliaccio A
中科院分区：
文献类型：
--
作者：
Castoria G;Giovannelli P;Di Donato M;Ciociola A;Hayashi R;Bernal F;Appella E;Auricchio F;Migliaccio A
尽管基质细胞在器官发育和疾病中的重要性已被证实，但基质细胞中雄激素受体（AR）的功能仍存在争议。在这里，我们表明，生理雄激素浓度（10 nM R1881或DHT）未能诱导DNA合成，而它始终刺激间充质和转化间充质细胞的细胞迁移。10纳摩尔R1881触发p27 Ser 10磷酸化及其在NIH 3 T3成纤维细胞中的稳定化。Rac及其下游效应物DYRK 1B的激活负责p27 Ser 10磷酸化和细胞静止。10纳摩尔雄激素也抑制NIH 3 T3成纤维细胞中致癌Ras诱导的转化。不能与细丝蛋白A相互作用的AR突变体的过表达、小肽置换AR/细丝蛋白A相互作用的使用以及细丝蛋白A敲低表明雄激素触发的AR/细丝蛋白A复合物调节导致p27 Ser 10磷酸化和细胞周期停滞的途径。由于AR/细丝蛋白A复合物也负责由10 nM雄激素刺激的迁移，我们的报告表明，雄激素触发的AR/细丝蛋白A复合物通过Rac 1控制细胞停止细胞周期和迁移的决定。这项研究揭示了雄激素/AR信号在协调基质细胞功能中的一个新的和意想不到的作用。
The functions of androgen receptor (AR) in stromal cells are still debated in spite of the demonstrated importance of these cells in organ development and diseases. Here, we show that physiological androgen concentration (10 nM R1881 or DHT) fails to induce DNA synthesis, while it consistently stimulates cell migration in mesenchymal and transformed mesenchymal cells. Ten nanomolar R1881 triggers p27 Ser10 phosphorylation and its stabilization in NIH3T3 fibroblasts. Activation of Rac and its downstream effector DYRK 1B is responsible for p27 Ser10 phosphorylation and cell quiescence. Ten nanomolar androgen also inhibits transformation induced by oncogenic Ras in NIH3T3 fibroblasts. Overexpression of an AR mutant unable to interact with filamin A, use of a small peptide displacing AR/filamin A interaction, and filamin A knockdown indicate that the androgen-triggered AR/filamin A complex regulates the pathway leading to p27 Ser10 phosphorylation and cell cycle arrest. As the AR/filamin A complex is also responsible for migration stimulated by 10 nM androgen, our report shows that the androgen-triggered AR/filamin A complex controls, through Rac 1, the decision of cells to halt cell cycle and migration. This study reveals a new and unexpected role of androgen/AR signalling in coordinating stromal cell functions.