Cyclin D3/CDK11p58 complex is involved in the repression of androgen receptor
Cyclin D3/CDK11p58 complex is involved in the repression of androgen receptor
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DOI：
10.1128/mcb.01753-06
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发表时间：
2007-10-01
影响因子：
5.3
通讯作者：
Gu, Jianxin
中科院分区：
文献类型：
--
作者：
Zong, Hongliang;Chi, Yayun;Gu, Jianxin
雄激素受体（AR）对于维持男性生殖系统至关重要，并且对于人类前列腺癌（PCas）的致癌作用至关重要。 D型细胞周期蛋白与AR功能的抑制密切相关。已有充分证据表明，cyclin D1 通过多种机制抑制 AR 功能，但 cyclin D3 在 AR 信号通路中发挥抑制作用的机制仍有待确定。在本研究中，我们证明细胞周期蛋白 D3 和细胞周期蛋白依赖性激酶 11 (CDK11(p58)) 的 58 kDa 亚型抑制 AR 转录活性，这是通过转化细胞和 PCa 细胞中前列腺特异性抗原表达的报告基因测定来测量的。 AR、细胞周期蛋白D3和CDK11(p58)在细胞内形成三元复合物，并共定位于前列腺管腔上皮层。 AR 活性由特定位点的磷酸化控制。我们发现 AR 在体外和体内均被 cyclin D3/CDK11(p58) 在 Ser-308 位点磷酸化，导致 AR 转录激活单元 1 (TAU1) 的活性受到抑制。此外，细胞周期蛋白 D3/CDK11(p58) 通过 AR 抑制来抑制 PCa 细胞的激素依赖性增殖。这些数据表明cyclin D3/CDK11(p58)信号传导参与AR功能的负调节。
Androgen receptor (AR) is essential for the maintenance of the male reproductive systems and is critical for the carcinogenesis of human prostate cancers (PCas). D-type cyclins are closely related to the repression of AR function. It has been well documented that cyclin D1 inhibits AR function through multiple mechanisms, but the mechanism of how cyclin D3 exerts its repressive role in the AR signaling pathway remains to be identified. In the present investigation, we demonstrate that cyclin D3 and the 58-kDa isoform of cyclin-dependent kinase 11 (CDK11(p58)) repressed AR transcriptional activity as measured by reporter assays of transformed cells and prostate-specific antigen expression in PCa cells. AR, cyclin D3, and CDK11(p58) formed a ternary complex in cells and were colocalized in the luminal epithelial layer of the prostate. AR activity is controlled by phosphorylation at specific sites. We found that AR was phosphorylated at Ser-308 by cyclin D3/CDK11(p58) in vitro and in vivo, leading to the repressed lactivity of AR transcriptional activation unit 1 (TAU1). Furthermore, and rogen-dependent proliferation of PCa cells was inhibited by cyclin D3/CDK11(p58) through AR repression. These data suggest that cyclin D3/CDK11(p58) signaling is involved in the negative regulation of AR function.