Tripartite Motif Containing 24 Acts as a Novel Coactivator of the Constitutive Active/Androstane Receptor
Tripartite Motif Containing 24 Acts as a Novel Coactivator of the Constitutive Active/Androstane Receptor
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DOI：
10.1124/dmd.117.077693
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发表时间：
2018-01-01
影响因子：
3.9
通讯作者：
Inouye, Yoshio
中科院分区：
文献类型：
--
作者：
Kanno, Yuichiro;Kure, Yuki;Inouye, Yoshio
组成型雄烷受体（CAR）是一种核受体，其充当多种基因的转录因子，包括编码异生素、类固醇和药物代谢酶和转运蛋白的基因。转录因子对靶基因的反式激活通常是通过协调和逐步募集各种称为辅调节因子的蛋白质介导的，包括辅激活因子和辅阻遏因子。在这项研究中，TRIM 24（也称为转录中介因子1 α）被发现与CAR相互作用。TRIM 24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CAR依赖性反式激活。这种增强在类固醇受体共激活因子（SRC）1或SRC 2的存在下协同增强，这两者都是CAR的共激活因子。此外，TRIM 24与CAR一起被募集到CYP 2B 6启动子的CAR结合元件。我们还注意到，TRIM 24的敲低抑制了HepTR/CAR和HepaRG细胞中CAR诱导的CYP 2B 6 mRNA表达，并抑制了HepaRG细胞中CAR诱导的CYP 3A 4 mRNA表达，但没有抑制HepTR/CAR细胞。根据这些结果，我们认为TRIM 24是一种新的CAR共激活因子，参与细胞和/或启动子选择性的反式激活。
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 togetherwith 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 theCARthat is involved in cell-and/ or promoter-selective transactivation.