Extracellular signal-regulated kinase 1/2 signaling pathway is required for endometrial decidualization in mice and human.
Extracellular signal-regulated kinase 1/2 signaling pathway is required for endometrial decidualization in mice and human.
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DOI：
10.1371/journal.pone.0075282
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Jeong JW
中科院分区：
文献类型：
--
作者：
Lee CH;Kim TH;Lee JH;Oh SJ;Yoo JY;Kwon HS;Kim YI;Ferguson SD;Ahn JY;Ku BJ;Fazleabas AT;Lim JM;Jeong JW
蜕膜化是成功胚胎植入和维持妊娠所需的关键变化。在此过程中，子宫内膜间质细胞分化为蜕膜细胞，以响应早期妊娠的卵巢类固醇激素。细胞外信号调节蛋白激酶1和2（ERK 1/2）已知在多种细胞类型中调节细胞增殖和凋亡，包括子宫内膜细胞。ERK 1/2的异常激活最近被认为与子宫内膜异位症和子宫内膜癌的病理过程有关。然而，ERK 1/2信号通路在着床和蜕膜化过程中的作用仍不清楚。为了确定ERK 1/2信号传导在着床和蜕膜化过程中的作用和调节，我们使用免疫染色和qPCR检测了小鼠妊娠早期子宫中的ERK 1/2信号传导。有趣的是，磷酸化ERK 1/2水平在位于着床部位的蜕膜细胞中最高。ERK 1/2靶基因的表达水平也显着更高的植入位点，相比，任何植入间的网站。为了确定ERK 1/2信号在人子宫内膜蜕膜化过程中是否也很重要，我们检测了体外培养的人子宫内膜间质细胞在蜕膜化过程中磷酸化ERK 1/2的水平。在用一种成熟的诱导蜕膜化的类固醇合成鸡尾酒治疗后，磷酸化ERK 1/2的水平显著增加。用ERK 1/2抑制剂U 0126处理显著降低了已知的蜕膜化标记基因IGFBP 1和PRL的表达，并抑制了已知的ERK 1/2靶基因FOS、MSK 1、STAT 1和STAT 3的诱导。有趣的是，CCAAT/增强子结合蛋白β（C/EBPβ）的磷酸化水平在该模型中显著降低，该蛋白先前被证明是蜕膜化的关键蛋白。这些结果表明，ERK 1/2信号转导是小鼠以及人子宫内膜基质细胞成功蜕膜化所必需的，并暗示C/EBPβ是ERK 1/2的下游靶点。
Decidualization is a crucial change required for successful embryo implantation and the maintenance of pregnancy. During this process, endometrial stromal cells differentiate into decidual cells in response to the ovarian steroid hormones of early pregnancy. Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) are known to regulate cell proliferation and apoptosis in multiple cell types, including uterine endometrial cells. Aberrant activation of ERK1/2 has recently been implicated in the pathological processes of endometriosis and endometrial cancer. However, the function of ERK1/2 signaling during implantation and decidualization is still unknown. To determine the role and regulation of ERK1/2 signaling during implantation and decidualization, we examine ERK1/2 signaling in the mouse uterus during early pregnancy using immunostaining and qPCR. Interestingly, levels of phospho-ERK1/2 were highest within decidual cells located at the implantation sites. Expression levels of ERK1/2 target genes were also significantly higher at implantation sites, when compared to either inter-implantation sites. To determine if ERK1/2 signaling is also important during human endometrial decidualization, we examined levels of phospho-ERK1/2 in cultured human endometrial stromal cells during in vitro decidualization. Following treatment with a well-established decidualization-inducing steroidogenic cocktail, levels of phospho-ERK1/2 were markedly increased. Treatment with the ERK1/2 inhibitor, U0126, significantly decreased the expression of the known decidualization marker genes, IGFBP1 and PRL as well as inhibited the induction of known ERK1/2 target genes; FOS, MSK1, STAT1, and STAT3. Interestingly, the phosphorylation level of CCAAT/ enhancer binding protein β (C/EBPβ), a protein previously shown to be critical for decidualization, was significantly reduced in this model. These results suggest that ERK1/2 signaling is required for successful decidualization in mice as well as human endometrial stromal cells and implicates C/EBPβ as a downstream target of ERK1/2.
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DOI：
10.1126/science.1171396
发表时间：
2009-05-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fan HY;Liu Z;Shimada M;Sterneck E;Johnson PF;Hedrick SM;Richards JS
通讯作者：
Richards JS
影响因子：
4
作者：
Laird, Susan;Tuckerman, E. M.;Li, T-C
通讯作者：
Li, T-C
影响因子：
4.8
作者：
Franco, Heather L.;Dai, Daisy;DeMayo, Francesco J.
通讯作者：
DeMayo, Francesco J.
影响因子：
16
作者：
Buck, M;Poli, V;Hunter, T
通讯作者：
Hunter, T
影响因子：
--
作者：
Fan, Heng-Yu;Liu, Zhilin;Richards, JoAnne S.
通讯作者：
Richards, JoAnne S.