Novosibirsk State University, Novosibirsk, Pirogova Street, 1, 630090, Russia; Federal Research Center of Fundamental and Translational Medicine, Novosibirsk, Timakova Street, 2/12, 630117, Russia.
Novosibirsk State University, Novosibirsk, Pirogova Street, 1, 630090, Russia.
Biochem Biophys Res Commun. 2018 Oct 2;504(2):361-366. doi: 10.1016/j.bbrc.2018.06.032. Epub 2018 Jun 11.
It was shown that CAR participates in the regulation of many cell processes. Thus, the activation of CAR causes a proliferating effect in the liver, which provides grounds to consider CAR as a therapeutic target when having a partial resection of this organ. Even though a lot of work has been done on the function of CAR in regulating hepatocyte proliferation, very little has been done on its complex mediating mechanism. This study, therefore, showed that the liver growth resulting from CAR activation leads to the decline in the level of PTEN protein and subsequent Akt activation in mouse liver. The increase of Akt activation produced by CAR agonist was accompanied by a decrease in the level of Foxo1, which was correlated with decreased expression of Foxo1 target genes, including Cdkn1a(p21). Moreover, the study also demonstrated that there exists a negative regulatory impact of CAR on the relationship between Foxo1 and targeted Cdkn1a(p21) promoter. Therefore, the study results revealed an essential function of CAR-Akt-Foxo1 signalling pathway in controlling hepatocyte proliferation by repressing the cell cycle regulator Cdkn1a (p21).
已证实，细胞凋亡抑制因子受体（CAR）参与许多细胞过程的调节。因此，CAR 的激活会导致肝脏增殖，这为部分切除该器官时将 CAR 视为治疗靶点提供了依据。尽管已经对 CAR 在调节肝细胞增殖中的功能进行了大量研究，但对其复杂的介导机制却知之甚少。因此，本研究表明，CAR 激活导致的肝脏生长导致鼠肝中 PTEN 蛋白水平下降和 Akt 激活。CAR 激动剂引起的 Akt 激活增加伴随着 Foxo1 水平的降低，这与 Foxo1 靶基因包括 Cdkn1a(p21)的表达降低有关。此外，该研究还表明，CAR 对 Foxo1 与靶向 Cdkn1a(p21)启动子之间关系存在负向调节作用。因此，研究结果揭示了 CAR-Akt-Foxo1 信号通路通过抑制细胞周期调节因子 Cdkn1a(p21)来控制肝细胞增殖的重要功能。
