Knudsen K E, Cavenee W K, Arden K C
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla 92093-0660, USA.
Cancer Res. 1999 May 15;59(10):2297-301.
D-type cyclins regulate distinct cellular processes, such as mitotic cell cycle control, differentiation, and transcription. We have previously shown that the D-type cyclins are critical for the androgen-dependent proliferation of prostate cells. Here, we sought to determine whether cyclin D1 directly influences the transactivation potential of the androgen receptor, a transcription factor that strongly influences androgen-dependent proliferation. We found that ligand-mediated transcriptional activation of a physiological target, prostate-specific antigen, by the androgen receptor was inhibited by cyclins D1 and D3. The ability of D-type cyclins to inhibit androgen receptor transactivation was not shared with other cyclins, and cyclin D1 was as effective as dominant negative mutants of the androgen receptor in inhibiting transactivation. This function of cyclin D1 was independent of its role in cell cycle progression and is likely elicited through its ability to form a specific complex with the androgen receptor. These data underscore the various mechanisms through which the androgen receptor is regulated and also point to a negative feedback role for cyclin D1 in controlling androgen-dependent growth.
D型细胞周期蛋白调节不同的细胞过程，如有丝分裂细胞周期控制、分化和转录。我们之前已经表明，D型细胞周期蛋白对于前列腺细胞的雄激素依赖性增殖至关重要。在此，我们试图确定细胞周期蛋白D1是否直接影响雄激素受体的反式激活潜能，雄激素受体是一种对雄激素依赖性增殖有强烈影响的转录因子。我们发现，细胞周期蛋白D1和D3可抑制雄激素受体对生理靶标前列腺特异性抗原的配体介导的转录激活。D型细胞周期蛋白抑制雄激素受体反式激活的能力并非其他细胞周期蛋白所共有，并且细胞周期蛋白D1在抑制反式激活方面与雄激素受体的显性负性突变体一样有效。细胞周期蛋白D1的这一功能独立于其在细胞周期进程中的作用，并且可能是通过其与雄激素受体形成特定复合物的能力引发的。这些数据强调了雄激素受体受到调节的多种机制，也指出了细胞周期蛋白D1在控制雄激素依赖性生长中的负反馈作用。
