FOXO1 mediates hypoxia-induced G0/G1 arrest in ovarian somatic granulosa cells via activating the TP53INP1-p53-CDKN1A pathway

文献类型： 外文期刊

第一作者： Li, Chengyu

作者： Li, Chengyu;Liu, Zhaojun;Wu, Gang;Zang, Ziyu;Li, Xiaoxuan;Tao, Jingli;Shen, Ming;Liu, Honglin;Zhang, Jia-Qing

作者机构：

关键词： Cell cycle; G0/G1 arrest; Porcine granulosa cells; Hypoxia; FOXO1-TP53INP1 signaling

期刊名称：DEVELOPMENT （ 影响因子：6.862； 五年影响因子：7.799 ）

ISSN： 0950-1991

年卷期： 2021 年 148 卷 14 期

页码：

收录情况： SCI

摘要： The development of ovarian follicles constitutes the foundation of female reproduction. The proliferation of granulosa cells (GCs) is a basic process required to ensure normal follicular development. However, the mechanisms involved in controlling GC cell cycle are not fully understood. Here, by performing gene expression profiling, we showed that cell cycle arrest at G0/G1 phase is highly correlated with pathways associated with hypoxic stress and FOXO signalling. Specifically, the elevated proportion of GCs at the arrested G0/G1 phase was accompanied by increased nuclear translocation of FOXO1 under conditions of hypoxia both in vivo and in vitro. Actually, phosphorylation of 14-3-3 by the JNK kinase is required for hypoxia-mediated FOXO1 activation and the resultant G0/G1 arrest. Notably, FOXO1 mutant without DNA-binding activity failed to induce G0/G1 arrest of GCs during hypoxia. Importantly, we identified a new target gene of FOXO1, namely TP53INP1, which contributed to the suppression of the G1-S cell cycle transition in response to hypoxia. Furthermore, we demonstrated that the inhibitory effect of the FOXO1-TP53INP1 axis on GC cell cycle is mediated through a p53-CDKN1A-dependent mechanism. These findings might provide avenues for the clinical treatment of human infertility caused by impaired follicular development.

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