Maoming People's Hospital, China.
Gene. 2023 Jun 30;871:147400. doi: 10.1016/j.gene.2023.147400. Epub 2023 Apr 5.
Cell cycle modulation is an important event during decidualization. E2F2 is a transcription regulator that plays a vital role in cell cycle regulation. However, the biological role of E2F2 in decidualization has not yet been identified. In this study, estrogen (E2) and progestin (P4)-induced in vitro and in vivo decidualization models were applied. Our data showed that the expression levels of E2F2 and its downstream target MCM4 were downregulated in the uterus tissues of E2P4-treated mice compared with control mice. In hESCs, exposure to E2P4 resulted in a significant decrease in E2F2 and MCM4 expression. E2P4 treatment reduced hESC proliferation and ectopic expression of E2F2 or MCM4 elevated the viability of E2P4-treated hESCs. In addition, ectopic expression of E2F2 or MCM4 restored the expression of G1 phase-associated proteins. The ERK pathway was inactivated in E2P4-treated hESCs. Treatment with ERK agonist Ro 67-7476 restored the expression of E2F2, MCM4, and G1 phase-associated proteins that were inhibited by E2P4. Moreover, Ro 67-7476 retracted the levels of IGFBP1 and PRL that were induced by E2P4. Collectively, our results indicate that E2F2 is regulated by ERK signaling and contributes to decidualization via regulation of MCM4. Therefore, E2F2/MCM4 cascade may serve as promising targets for alleviating decidualization dysfunction.
细胞周期调控是蜕膜化过程中的一个重要事件。E2F2 是一种转录调节因子，在细胞周期调控中起着至关重要的作用。然而，E2F2 在蜕膜化中的生物学作用尚未确定。在本研究中，应用了雌激素（E2）和孕激素（P4）诱导的体外和体内蜕膜化模型。我们的数据显示，与对照组小鼠相比，E2P4 处理的小鼠子宫组织中 E2F2 及其下游靶标 MCM4 的表达水平下调。在 hESC 中，暴露于 E2P4 导致 E2F2 和 MCM4 的表达显著降低。E2P4 处理减少了 hESC 的增殖，而过表达 E2F2 或 MCM4 则提高了 E2P4 处理的 hESC 的活力。此外，过表达 E2F2 或 MCM4 恢复了 G1 期相关蛋白的表达。E2P4 处理的 hESC 中 ERK 通路失活。用 ERK 激动剂 Ro 67-7476 处理可恢复被 E2P4 抑制的 E2F2、MCM4 和 G1 期相关蛋白的表达。此外，Ro 67-7476 降低了 E2P4 诱导的 IGFBP1 和 PRL 的水平。综上所述，我们的研究结果表明，E2F2 受 ERK 信号通路调节，通过调节 MCM4 促进蜕膜化。因此，E2F2/MCM4 级联可能成为缓解蜕膜化功能障碍的有前途的靶点。
