Department of Pathology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
J Cell Sci. 2012 Apr 15;125(Pt 8):1970-9. doi: 10.1242/jcs.096792. Epub 2012 Feb 10.
Androgen-regulated gene expression is a highly coordinated dynamic process mediated by androgen receptor (AR) ligand binding and DNA binding, and by specific AR protein-protein interactions. The latter include DNA-binding domain (D-box) interactions in AR homodimers, and the interaction of the FQNLF motif in the AR N-terminal domain and the coactivator groove in the ligand-binding domain (N/C interaction). We have studied these interactions in AR homodimerization using quantitative imaging techniques. We found that the initial cytoplasmic intramolecular AR N/C interaction after ligand binding is followed by a D-box-dimerization-dependent transition to intermolecular N/C interaction in a proportion of nuclear ARs. The consecutive steps leading to homodimerization are initiated prior to DNA binding. Our data indicate the presence of nuclear pools of both AR homodimers and monomers. On the basis of AR-regulated reporter assays we propose specificity in regulation of gene expression by AR homodimers and monomers mediated by AR domain interactions. Moreover, our findings elucidate important steps in the spatiotemporal organization of AR intra- and inter-molecular interactions.
雄激素调节的基因表达是一个高度协调的动态过程，由雄激素受体 (AR) 的配体结合和 DNA 结合以及特定的 AR 蛋白-蛋白相互作用介导。后者包括 AR 同源二聚体中的 DNA 结合域 (D 盒) 相互作用，以及 AR N 端结构域中的 FQNLF 基序与配体结合域中的共激活因子槽 (N/C 相互作用) 的相互作用。我们使用定量成像技术研究了 AR 同源二聚化中的这些相互作用。我们发现，配体结合后细胞质内 AR 分子内 N/C 相互作用的初始阶段之后，在一部分核 AR 中，D 盒二聚化依赖性地转变为分子间 N/C 相互作用。导致同源二聚化的连续步骤在 DNA 结合之前就开始了。我们的数据表明，存在 AR 同源二聚体和单体的核池。基于 AR 调节的报告基因检测，我们提出 AR 同源二聚体和单体通过 AR 结构域相互作用介导的基因表达调控具有特异性。此外，我们的发现阐明了 AR 分子内和分子间相互作用的时空组织中的重要步骤。
