Lan Zi-Jian, Krause M S, Redding S D, Li X, Wu G Z, Zhou H X, Bohler H C, Ko C, Cooney A J, Zhou Junmei, Lei Z M
Division of Life Sciences and Center for Animal Nutrigenomics & Applied Animal Nutrition, Alltech Inc., Nicholasville, KY 40356, USA.
Department of OB/GYN & Women's Health, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Mol Cell Endocrinol. 2017 Mar 15;444:26-37. doi: 10.1016/j.mce.2017.01.043. Epub 2017 Jan 28.
Theca cell-selective Pten mutation (tPtenMT) in mice resulted in increases in PDK1 and Akt phosphorylation, indicating an over-activation of PI3K signaling in the ovaries. These mice displayed elevated androgen levels, ovary enlargement, antral follicle accumulation, early fertility loss and increased expression of Lhcgr and genes that are crucial to androgenesis. These abnormalities were partially reversed by treatments of PI3K or Akt inhibitor. LH actions in Pten deficient theca cells were potentiated. The phosphorylation of Foxo1 was increased, while the binding of Foxo1 to forkhead response elements in the Lhcgr promoter was reduced in tPtenMT theca cells, implying a mechanism by which PI3K/Akt-induced upregulation of Lhcgr in theca cells might be mediated by reducing the inhibitory effect of Foxo1 on the Lhcgr promoter. The phenotype of tPtenMT females is reminiscent of human PCOS and suggests that dysregulated PI3K cascade in theca cells may be involved in certain types of PCOS pathogenesis.
小鼠中卵泡膜细胞选择性Pten突变（tPtenMT）导致PDK1和Akt磷酸化增加，表明卵巢中PI3K信号过度激活。这些小鼠表现出雄激素水平升高、卵巢增大、窦状卵泡积聚、早期生育力丧失以及Lhcgr和对雄激素生成至关重要的基因表达增加。PI3K或Akt抑制剂治疗可部分逆转这些异常。在Pten缺陷的卵泡膜细胞中，LH的作用增强。在tPtenMT卵泡膜细胞中，Foxo1的磷酸化增加，而Foxo1与Lhcgr启动子中叉头反应元件的结合减少，这意味着PI3K/Akt诱导的卵泡膜细胞中Lhcgr上调的机制可能是通过减少Foxo1对Lhcgr启动子的抑制作用来介导的。tPtenMT雌性小鼠的表型使人联想到人类多囊卵巢综合征（PCOS），并表明卵泡膜细胞中PI3K级联失调可能参与某些类型的PCOS发病机制。
