Prokineticin 1 signaling and gene regulation in early human pregnancy.

Prokineticin 1 signaling and gene regulation in early human pregnancy.
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DOI:
10.1210/en.2007-1633
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发表时间:
2008-06
期刊:
影响因子:
4.8
通讯作者:
Jabbour HN
Jabbour HN
中科院分区:
医学2区
文献类型:
--
作者:
Evans J;Catalano RD;Morgan K;Critchley HO;Millar RP;Jabbour HN

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前动力蛋白1(Prokineticin 1,PROK 1)是一种新近发现的蛋白质,具有广泛的功能,包括组织特异性血管生成、炎症反应调节和造血调节。本研究的目的是探讨PROK 1和促动素受体1(PROKR 1)在人早孕子宫内膜中的作用。与非妊娠子宫内膜相比,PROK 1和PROKR 1在妊娠早期蜕膜中的表达显著升高。PROK 1和PROKR 1的表达定位于腺上皮和间质内的各种细胞区室。为了研究PROK 1激活的信号通路和靶基因,我们建立了稳定表达PROKR 1的子宫内膜上皮细胞系(石川PROKR 1细胞)。PROK 1-PROKR 1相互作用诱导磷酸肌醇动员和c-Src、表皮生长因子受体和ERK 1/2的顺序磷酸化。从用40 nm PROK 1处理8 h的石川PROKR 1细胞中提取的RNA的基因微阵列分析揭示了49个差异调节的基因。这些基因中的许多基因,包括环氧合酶(考克斯)-2、白血病抑制因子、IL-6、IL-8和IL-11,在着床和早期妊娠的子宫内膜中受到调节。我们随后研究了PROK 1对石川PROKR 1细胞和早孕蜕膜中考克斯-2表达的影响。考克斯-2 mRNA和蛋白质表达以及前列腺素合成在PROK 1治疗后升高。此外,PROK 1对考克斯-2的表达依赖于Gq-磷脂酶C-β-cSrc-表皮生长因子受体-MAPK/ERK激酶通路的激活。这些数据表明,PROK 1和PROKR 1的表达是在人类早孕蜕膜中升高,PROK 1-PROKR 1相互作用调节了许多流产相关基因的表达。
Prokineticin 1 (PROK1) is a recently described protein with a wide range of functions including tissue-specific angiogenesis, modulation of inflammatory responses, and regulation of hematopoiesis. The objective of this study was to investigate the role of PROK1 and prokineticin receptor 1 (PROKR1) in human endometrium during early pregnancy. PROK1 and PROKR1 expression is significantly elevated in first-trimester decidua, compared with nonpregnant endometrium. Expression of PROK1 and PROKR1 was localized in glandular epithelial and various cellular compartments within the stroma. To investigate the signaling pathways and target genes activated by PROK1, we generated an endometrial epithelial cell line stably expressing PROKR1 (Ishikawa PROKR1 cells). PROK1-PROKR1 interaction induced inositol phosphate mobilization and sequential phosphorylation of c-Src, epidermal growth factor receptor, and ERK 1/2. Gene microarray analysis on RNA extracted from Ishikawa PROKR1 cells treated with 40 nm PROK1 for 8 h revealed 49 genes to be differentially regulated. A number of these genes, including cyclooxygenase (COX)-2, leukemia inhibitory factor, IL-6, IL-8, and IL-11 are regulated in the endometrium during implantation and early pregnancy. We subsequently investigated the effect of PROK1 on expression of COX-2 in Ishikawa PROKR1 cells and first-trimester decidua. COX-2 mRNA and protein expression, and prostaglandin synthesis, were elevated in response to treatment with PROK1. Moreover, expression of COX-2 by PROK1 was dependent on activation of the Gq-phospholipase C-β-cSrc-epidermal growth factor receptor-MAPK/ERK kinase pathway. These data demonstrate that PROK1 and PROKR1 expression is elevated in human decidua during early pregnancy and that PROK1-PROKR1 interaction regulates expression of a host of implantation-related genes.
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