Institute of Molecular Biology and Biophysics SB RAMS, Timakova str. 2, Novosibirsk 630117, Russia.
Institute of Molecular Biology and Biophysics SB RAMS, Timakova str. 2, Novosibirsk 630117, Russia; Novosibirsk State University, Pirogova str. 2, Novosibirsk 630090, Russia.
Toxicology. 2014 Jul 3;321:73-9. doi: 10.1016/j.tox.2014.04.003. Epub 2014 Apr 24.
1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), an agonist of constitutive androstane receptor (CAR), is a well-known strong primary chemical mitogen for the mouse liver. Despite extensive investigation of the role of CAR in the regulation of cell proliferation, our knowledge of the intricate mediating mechanism is incomplete. In this study, we demonstrated that long-term CAR activation by TCPOBOP increased liver-to-body weight ratio and decreased tumour suppressor Foxo1 expression and transcriptional activity, which were correlated with reduced expression of genes regulated by Foxo1, including the cell-cycle inhibitor Cdkn1a(p21), and upregulation of the cell-cycle regulator Cyclin D1. Moreover, we demonstrated the negative regulatory effect of TCPOBOP-activated CAR on the association of Foxo1 with the target Foxo1 itself and Cdkn1a(p21) promoters. Thus, we identified CAR-mediated repression of cell cycle inhibitor p21, as mediated by repression of FOXO1 expression and transcriptional activity. CAR-FOXO1 cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments.
1,4-双[2-(3,5-二氯吡啶氧基)]苯（TCPOBOP）是一种组成型雄烷受体（CAR）激动剂，是一种众所周知的强烈原发性化学肝有丝分裂原。尽管人们对 CAR 在细胞增殖调节中的作用进行了广泛的研究，但我们对其复杂的介导机制仍了解甚少。在这项研究中，我们证明了 TCPOBOP 对 CAR 的长期激活会增加肝体比，并降低肿瘤抑制因子 Foxo1 的表达和转录活性，这与 Foxo1 调节的基因表达减少有关，包括细胞周期抑制剂 Cdkn1a(p21)，以及细胞周期调节剂 Cyclin D1 的上调。此外，我们证明了 TCPOBOP 激活的 CAR 对 Foxo1 与靶 Foxo1 自身和 Cdkn1a(p21)启动子结合的负调节作用。因此，我们确定了 CAR 介导的细胞周期抑制剂 p21 的抑制作用，这是通过抑制 FOXO1 的表达和转录活性介导的。CAR-FOXO1 相互作用可能为理解肝脏疾病和开发更有效的治疗方法提供新的机会，以实现更好的药物治疗。
