Forman B M, Tzameli I, Choi H S, Chen J, Simha D, Seol W, Evans R M, Moore D D
The City of Hope National Medical Center, Duarte, California 91010, USA.
Nature. 1998 Oct 8;395(6702):612-5. doi: 10.1038/26996.
The orphan receptor CAR-beta binds DNA as a heterodimer with the retinoid-X receptor and activates gene transcription in a constitutive manner. Here we show that, in contrast to the classical nuclear receptors, the constitutive activity of CAR-beta results from a ligand-independent recruitment of transcriptional co-activators. While searching for potential ligands of CAR-beta, we found that the steroids androstanol and androstenol inhibit the constitutive activity of CAR-beta. This effect is stereospecific: only 3alpha-hydroxy, 5alpha-reduced androstanes are active. These androstanes do not interfere with heterodimerization or DNA binding of CAR-beta; instead, they promote co-activator release from the ligand-binding domain. These androstane ligands are examples of naturally occurring inverse agonists that reverse transcriptional activation by nuclear receptors. CAR-beta (constitutive androstane receptor-beta), therefore, defines an unanticipated steroidal signalling pathway that functions in a manner opposite to that of the conventional nuclear receptor pathways.
孤儿受体CAR-β与视黄酸X受体形成异二聚体结合DNA，并以组成型方式激活基因转录。我们在此表明，与经典核受体不同，CAR-β的组成型活性源于转录共激活因子的非配体依赖性募集。在寻找CAR-β的潜在配体时，我们发现甾体雄烷醇和雄烯醇可抑制CAR-β的组成型活性。这种效应具有立体特异性：只有3α-羟基、5α-还原雄烷具有活性。这些雄烷并不干扰CAR-β的异二聚化或DNA结合；相反，它们促进共激活因子从配体结合域释放。这些雄烷配体是天然存在的反向激动剂的例子，可逆转核受体的转录激活。因此，CAR-β（组成型雄烷受体-β）定义了一条意想不到的甾体信号通路，其作用方式与传统核受体通路相反。
