A central role for cAMP/EPAC/RAP/PI3K/AKT/CREB signaling in LH-induced follicular Pgr expression at medaka ovulation
A central role for cAMP/EPAC/RAP/PI3K/AKT/CREB signaling in LH-induced follicular Pgr expression at medaka ovulation
复制标题
cAMP/EPAC/RAP/PI 3 K/AKT/CREB信号在青鳉排卵时LH诱导的卵泡Pgr表达中的中心作用
DOI：
10.1093/biolre/ioab077
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发表时间：
2021-04-20
影响因子：
3.6
通讯作者：
Takahashi, Takayuki
中科院分区：
文献类型：
--
作者：
Ogiwara, Katsueki;Hoyagi, Miyuki;Takahashi, Takayuki
核受体是一种配体激活的转录因子，在卵巢和子宫功能的调节中起着重要作用，其活性的异常调控可导致不孕和癌症等疾病的发生。PGR在脊椎动物排卵中的重要作用是公认的，但在低等脊椎动物中，在排卵LH峰后在排卵前卵泡中快速和短暂诱导PGR的机制尚不清楚。为了解决这个问题，我们利用小型淡水硬骨鱼青鳉，这是一个很好的模型系统，研究脊椎动物排卵。在离体排卵系统中，我们发现EPAC（Brefeldin A）、RAP（GGTI 298）、PI 3 K（Wortmannin）、AKT（AKT inhibitor IV）和CREB（KG-501）抑制LH诱导的卵泡排卵，而PKA抑制剂H-89对卵泡排卵没有影响。能够抑制卵泡排卵的抑制剂也抑制Pgr和基质金属蛋白酶-15（Mmp 15）的卵泡表达，后者先前被证明不仅是Pgr的下游效应子，而且是青鳉排卵中卵泡破裂所必需的蛋白水解酶。进一步的详细分析首次揭示了cAMP/EPAC/RAP/PI 3 K/AKT/CREB信号通路介导LH信号诱导排卵前卵泡Pgr表达。我们的数据还表明，磷酸化Creb 1是一个转录因子必不可少的pgr的表达和Creb 1磷酸化的Akt 1，而不是PKA，可以优选地用于诱导pgr的expression.Summary EPAC/RAP/PI 3 K/AKT/CREB信号转导介导LH诱导的cAMP信号转导，以诱导青鳉Pgr的表达在排卵卵泡。
Nuclear progestin receptor (PGR) is a ligand-activated transcription factor that has been identified as a pivotal mediator of many processes associated with ovarian and uterine function, and aberrant control of PGR activity causes infertility and disease including cancer. The essential role of PGR in vertebrate ovulation is well recognized, but the mechanisms by which PGR is rapidly and transiently induced in preovulatory follicles after the ovulatory LH surge are not known in lower vertebrates. To address this issue, we utilized the small freshwater teleost medaka Oryzias latipes, which serves as a good model system for studying vertebrate ovulation. In the in vitro ovulation system using preovulatory follicles dissected from the fish ovaries, we found that inhibitors of EPAC (brefeldin A), RAP (GGTI298), PI3K (Wortmannin), AKT (AKT inhibitor IV), and CREB (KG-501) inhibited LH-induced follicle ovulation, while the PKA inhibitor H-89 had no effect on follicle ovulation. The inhibitors capable of inhibiting follicle ovulation also inhibited follicular expression of Pgr and matrix metalloproteinase-15 (Mmp15), the latter of which was previously shown to not only be a downstream effector of Pgr but also a proteolytic enzyme indispensable for follicle rupture in medaka ovulation. Further detailed analysis revealed for the first time that the cAMP/EPAC/RAP/PI3K/AKT/CREB signaling pathway mediates the LH signal to induce Pgr expression in preovulatory follicles. Our data also showed that phosphorylated Creb1 is a transcription factor essential for pgr expression and that Creb1 phosphorylated by Akt1, rather than PKA, may be preferably used to induce pgr expression.Summary sentenceEPAC/RAP/PI3K/AKT/CREB signaling mediates LH-induced cAMP signaling to induce medaka Pgr expression in ovulating follicles.