Ligand-specific dynamics of the androgen receptor at its response element in living cells
Ligand-specific dynamics of the androgen receptor at its response element in living cells
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DOI：
10.1128/mcb.01297-06
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发表时间：
2007-03-01
影响因子：
5.3
通讯作者：
Saatcioglu, Fahri
中科院分区：
文献类型：
--
作者：
Klokk, Tove I.;Kurys, Piotr;Saatcioglu, Fahri
雄激素在正常生理和男性性别分化以及前列腺癌等病理状况中发挥着关键作用。雄激素通过雄激素受体（AR）起作用，雄激素受体是一种配体调节的转录因子。抗雄激素阻断AR功能，广泛用于疾病状态，但对其体内作用机制知之甚少。在这里，我们描述了在激动剂存在的情况下，AR与活细胞中靶基因组位点的快速差异相互作用，这与BRM atp酶复合体的募集和染色质重塑相吻合，导致转录激活。相比之下，拮抗剂结合或突变AR与其靶标的相互作用在动力学上是不同的：它的相互作用要快得多，发生时没有染色质重塑，并导致缺乏转录抑制。野生型AR和激素应答元件转录受损突变体的荧光共振能量转移分析表明，与两个相邻AR的分子间相互作用相比，AR的N端和C端分子内相互作用在体内起关键作用。这些数据为活细胞中雄激素和抗雄激素调控基因表达提供了动力学和机制基础。
Androgens have key roles in normal physiology and in male sexual differentiation as well as in pathological conditions such as prostate cancer. Androgens act through the androgen receptor (AR), which is a ligand-modulated transcription factor. Antiandrogens block AR function and are widely used in disease states, but little is known about their mechanism of action in vivo. Here, we describe a rapid differential interaction of AR with target genomic sites in living cells in the presence of agonists which coincides with the recruitment of BRM ATPase complex and chromatin remodeling, resulting in transcriptional activation. In contrast, the interaction of antagonist-bound or mutant AR with its target was found to be kinetically different: it was dramatically faster, occurred without chromatin remodeling, and resulted in the lack of transcriptional inhibition. Fluorescent resonance energy transfer analysis of wild-type AR and a transcriptionally compromised mutant at the hormone response element showed that intramolecular interactions between the N and C termini of AR play a key functional role in vivo compared to intermolecular interactions between two neighboring ARs. These data provide a kinetic and mechanistic basis for regulation of gene expression by androgens and antiandrogens in living cells.