Sampson E R, Yeh S Y, Chang H C, Tsai M Y, Wang X, Ting H J, Chang C
Department of Pathology, and The Cancer Center, University of Rochester, NY, USA.
J Biol Regul Homeost Agents. 2001 Apr-Jun;15(2):123-9.
The androgen receptor (AR) is a member of the nuclear receptor (NR) superfamily that mediates the effects of androgens on target tissues. Over the last decade, it has become apparent that NRs require accessory factors for optimal activation of target gene expression. Numerous NR coregulators have been identified, with diverse structures and potential mechanisms of coregulation, creating an increasingly complicated picture of NR action. Due to the expanding complexity of the coregulator field, this review will focus on the AR ligand-binding domain (LBD) and N-terminal interacting proteins identified by our lab. The LBD-interacting proteins ARA70, ARA55 and ARA54 were first characterized and ARA70 was found to have a relatively higher specificity for the AR in human prostate cancer DU145 cells. Characterization of the functional relationship between the AR and these coregulators indicated that ARA70 and ARA55 could enhance the androgenic effects of 17beta-estradiol (E2) and hydroxyflutamide (HF), an antiandrogen commonly used in the treatment of prostate cancer. ARA160, an AR N-terminal interacting protein also known as TATA element modulatory factor (TMF), was subsequently shown to cooperate with ARA70 in enhancing AR activity. Another AR N-terminal interacting protein, ARA24, interacted with the poly-Q tract, a region within the N-terminus of the AR linked to Kennedy's disease (X-linked spinal and bulbar muscular atrophy). More recently, our lab has identified ARA267, a SET domain containing protein, and supervillin, an F-actin binding protein, as AR coregulators. Collectively, the data from these studies indicate that these coregulators are necessary for optimal AR transactivation. Interruption of the interaction between AR and these proteins may serve as a new therapeutic target in the treatment of prostate cancer.
雄激素受体（AR）是核受体（NR）超家族的成员，介导雄激素对靶组织的作用。在过去十年中，越来越明显的是，核受体需要辅助因子来实现靶基因表达的最佳激活。已经鉴定出许多核受体共调节因子，它们具有不同的结构和共调节的潜在机制，使得核受体作用的情况越来越复杂。由于共调节因子领域的复杂性不断增加，本综述将聚焦于我们实验室鉴定的AR配体结合域（LBD）和N端相互作用蛋白。首先对与LBD相互作用的蛋白ARA70、ARA55和ARA54进行了表征，并且发现ARA70在人前列腺癌DU145细胞中对AR具有相对较高的特异性。对AR与这些共调节因子之间功能关系的表征表明，ARA70和ARA55可以增强17β-雌二醇（E2）和羟基氟他胺（HF，一种常用于治疗前列腺癌的抗雄激素）的雄激素作用。ARA160，一种也被称为TATA元件调节因子（TMF）的AR N端相互作用蛋白，随后被证明在增强AR活性方面与ARA70协同作用。另一种AR N端相互作用蛋白ARA24与多聚谷氨酰胺序列相互作用，该序列是AR N端内与肯尼迪病（X连锁脊髓和延髓肌肉萎缩）相关的区域。最近，我们实验室已鉴定出含SET结构域的蛋白ARA267和F-肌动蛋白结合蛋白 supervillin作为AR共调节因子。总体而言，这些研究的数据表明，这些共调节因子对于AR的最佳反式激活是必需的。AR与这些蛋白之间相互作用的中断可能成为治疗前列腺癌的新治疗靶点。
