Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4965, USA.
J Mol Biol. 2010 Apr 16;397(5):1121-31. doi: 10.1016/j.jmb.2010.02.030. Epub 2010 Feb 24.
Ligands that activate the nuclear receptor retinoid X receptor (RXR) display potent anticarcinogenic activities, but the mechanisms by which these compounds inhibit carcinoma cell growth are poorly understood. While RXR can regulate gene expression due to its intrinsic ligand-activated transcription function, this receptor can also regulate transcription by functioning as a ligand-controlled DNA architectural factor. It was thus reported that apo-RXR self-associates into tetramers and that each dimer within these tetramers can separately bind to an RXR response element. Hence, DNA binding by RXR tetramers may bring distant genomic regions into close physical proximity. As ligand binding induces the dissociation of RXR tetramers into dimers, it can alter gene expression by modulating the DNA architecture. Here, we show that inhibition of mammary carcinoma cell growth by RXR ligands stems from the ability of these compounds to regulate the oligomeric state of RXR and is independent of the direct intrinsic transcriptional activity of the receptor. The data suggest that compounds that trigger dissociation of RXR tetramers may comprise a novel class of anticarcinogenic agents.
配体激活核受体视黄酸 X 受体（RXR）具有很强的抗癌活性，但这些化合物抑制癌细胞生长的机制还不清楚。虽然 RXR 可以通过其内在的配体激活转录功能来调节基因表达，但该受体也可以通过作为配体控制的 DNA 结构因子来调节转录。因此有报道称，apo-RXR 自身缔合成四聚体，这些四聚体中的每个二聚体都可以分别与 RXR 反应元件结合。因此，RXR 四聚体的 DNA 结合可能使远隔的基因组区域接近物理接近。由于配体结合诱导 RXR 四聚体解离成二聚体，它可以通过调节 DNA 结构来改变基因表达。在这里，我们表明 RXR 配体抑制乳腺癌细胞生长源于这些化合物调节 RXR 寡聚状态的能力，并且与受体的直接内在转录活性无关。这些数据表明，引发 RXR 四聚体解离的化合物可能构成一类新的抗癌药物。
