Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba, Japan
Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba, Japan.
Drug Metab Dispos. 2018 Jan;46(1):46-52. doi: 10.1124/dmd.117.077693. Epub 2017 Nov 3.
The constitutive androstane receptor (CAR) is a nuclear receptor that acts as a transcription factor for a variety of genes, including genes encoding xenobiotic, steroid, and drug-metabolizing enzymes and transporters. Transactivation of a target gene by a transcription factor is generally mediated through the concerted and stepwise recruitment of various proteins termed coregulators, including coactivators and corepressors. In this study, TRIM24 (also known as transcriptional intermediary factor 1 alpha) was found to interact with the CAR. TRIM24 enhanced the CAR-dependent transactivation in reporter assays using the direct repeat-4 motif, a binding site of the CAR. This enhancement was synergistically augmented in the presence of steroid receptor coactivator (SRC) 1 or SRC2, both of which are coactivators of the CAR. In addition, TRIM24 was recruited to the CAR-binding element of the CYP2B6 promoter together with the CAR. We also noted that knockdown of TRIM24 suppressed CAR-induced CYP2B6 mRNA expression in HepTR/CAR and HepaRG cells and suppressed CAR-induced CYP3A4 mRNA expression in HepaRG cells but not HepTR/CAR cells. From these results, we suggest that TRIM24 is a novel coactivator of the CAR that is involved in cell- and/or promoter- selective transactivation.
组成型雄烷受体（CAR）是一种核受体，作为多种基因的转录因子，包括编码外源物质、甾体和药物代谢酶和转运蛋白的基因。转录因子对靶基因的转录激活通常通过各种称为共激活因子的蛋白的协同和逐步募集来介导，包括共激活因子和核心抑制剂。在这项研究中，发现 TRIM24（也称为转录中介因子 1α）与 CAR 相互作用。TRIM24 在使用直接重复-4 基序（CAR 的结合位点）的报告基因测定中增强了 CAR 依赖性转录激活。在存在类固醇受体共激活因子（SRC）1 或 SRC2 的情况下，这种增强协同增加，SRC1 或 SRC2 均为 CAR 的共激活因子。此外，TRIM24 与 CAR 一起被募集到 CYP2B6 启动子的 CAR 结合元件上。我们还注意到，TRIM24 的敲低抑制了 HepTR/CAR 和 HepaRG 细胞中 CAR 诱导的 CYP2B6 mRNA 表达，并抑制了 HepaRG 细胞中而不是 HepTR/CAR 细胞中 CAR 诱导的 CYP3A4 mRNA 表达。从这些结果中，我们认为 TRIM24 是 CAR 的一种新型共激活因子，参与细胞和/或启动子选择性转录激活。
