Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation
Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation
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DOI：
10.1073/pnas.0506281103
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发表时间：
2006-02-14
影响因子：
11.1
通讯作者：
Knudsen, KE
中科院分区：
文献类型：
--
作者：
Burd, CJ;Petre, CE;Knudsen, KE
细胞周期蛋白D1是转录和细胞周期进程的多方面调节因子，存在于两种不同的亚型中，细胞周期蛋白D1a和D1b。在前列腺中，细胞周期蛋白D1a通过离散机制负调节雄激素受体（AR）活性，从而限制雄激素依赖性增殖。因此，细胞周期蛋白D1a很少在前列腺腺癌中过表达，并且在这种肿瘤类型中几乎没有预后价值。然而，一种常见的多态性（A870）已知有助于细胞周期蛋白D1b的产生与前列腺癌风险增加有关。在这里，我们表明，细胞周期蛋白D1b在前列腺癌中的高频率表达，并在肿瘤性疾病中上调。此外，我们的数据表明，虽然细胞周期蛋白D1b保留空气协会，它是选择性妥协的空气调节。通过使用体外和体内试验观察到细胞周期蛋白D1b调节AR的能力改变，并且与AIR依赖性增殖的调节受损相关。与以前的报道一致，细胞周期蛋白D1a的表达抑制AR依赖性前列腺癌细胞的细胞周期进展。引人注目的是，细胞周期蛋白D1b显着刺激这种细胞类型的增殖。AR阴性前列腺癌细胞对细胞周期蛋白D1（a或B）表达无反应，表明AIR辅阻遏物功能缺陷在AR依赖性细胞中产生特异性生长优势。总之，这些研究表明，细胞周期蛋白D1b的AR调节能力的改变有助于其与前列腺癌风险增加的相关性，并提供了细胞周期蛋白D1b介导的转录调节的证据。
Cyclin D1 is a multifaceted regulator of both transcription and cell-cycle progression that exists in two distinct isoforms, cyclin D1a and D1b. In the prostate, cyclin D1a acts through discrete mechanisms to negatively regulate androgen receptor (AR) activity and thus limit androgen-dependent proliferation. Accordingly, cyclin D1a is rarely overexpressed in prostatic adenocarcinoma and holds little prognostic value in this tumor type. However, a common polymorphism (A870) known to facilitate production of cyclin D1b is associated with increased prostate cancer risk. Here we show that cyclin D1b is expressed at high frequency in prostate cancer and is up-regulated in neoplastic disease. Furthermore, our data demonstrate that, although cyclin D1b retains AIR association, it is selectively compromised for AIR regulation. The altered ability of cyclin D1b to regulate the AR was observed by using both in vitro and in vivo assays and was associated with compromised regulation of AIR-dependent proliferation. Consistent with previous reports, expression of cyclin D1a inhibited cell-cycle progression in AR-dependent prostate cancer cells. Strikingly, cyclin D1b significantly stimulated proliferation in this cell type. AR-negative prostate cancer cells were nonresponsive to cyclin D1 (a or b) expression, indicating that defects in AIR corepressor function yield a growth advantage specifically in AR-dependent cells. In summary, these studies indicate that the altered AR regulatory capacity of cyclin D1b contributes to its association with increased prostate cancer risk and provide evidence of cyclin D1b-mediated transcriptional regulation.