Matrix metalloproteinase 9 is a distal-less 3 target-gene in placental trophoblast cells.
Matrix metalloproteinase 9 is a distal-less 3 target-gene in placental trophoblast cells.
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基质金属蛋白酶 9 是胎盘滋养层细胞中的远端较少的 3 靶基因。
DOI：
10.1152/ajpcell.00205.2012
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
Roberson,MarkS
中科院分区：
文献类型：
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作者：
Clark,PatriciaA;Xie,Jianjun;Li,Sha;Zhang,Xuesen;Coonrod,Scott;Roberson,MarkS
基质金属蛋白酶（MMP）是调节细胞外基质组成并促进细胞迁移的酶。在小鼠胎盘中的微阵列研究表明，MMP-9转录丰度依赖于胎盘特异性转录调节因子Distal-less 3（Dlx 3）;然而，尚不清楚这是直接还是间接的影响。在这里，我们研究胎盘滋养层细胞中Dlx 3依赖性MMP-9基因转录和明胶酶活性的机制。最初的研究证实，MMP-9活性在Dlx 3 −/−小鼠的胎盘外植体中降低，并且Dlx 3过表达诱导了小鼠MMP-9启动子活性。在鼠MMP-9启动子片段内的两个结合位点结合Dlx 3，并且两个元件中的突变降低了基础MMP-9-荧光素酶报告活性并废除了Dlx 3的调节。在JEG 3细胞中的染色质免疫沉淀研究证实了Dlx 3在三个不同位点与内源性人MMP-9启动子结合，并且敲低人Dlx 3导致内源性MMP-9转录物和分泌活性降低。这些研究提供了新的证据表明，Dlx 3直接参与小鼠和人胎盘滋养层细胞MMP-9基因表达的转录调控。
Matrix metalloproteinases (MMPs) are enzymes that regulate extracellular matrix composition and contribute to cell migration. Microarray studies in mouse placenta suggested that MMP-9 transcript abundance was dependent on distal-less 3 (Dlx3), a placental-specific transcriptional regulator; however, it was not clear if this was a direct or indirect effect. Here we investigate mechanism(s) for Dlx3-dependent MMP-9 gene transcription and gelatinase activity in placental trophoblasts. Initial studies confirmed that MMP-9 activity was reduced in placental explants from Dlx3−/−mice and that murine MMP-9 promoter activity was induced by Dlx3 overexpression. Two binding sites within a murine MMP-9 promoter fragment bound Dlx3, and mutations in both elements reduced basal MMP-9-luciferase reporter activity and abolished regulation by Dlx3. Chromatin immunoprecipitation studies in JEG3 cells confirmed Dlx3 binding to the endogenous human MMP-9 promoter at three distinct sites and knockdown of human Dlx3 resulted in reduced endogenous MMP-9 transcripts and secreted activity. These studies provide novel evidence that Dlx3 is involved directly in the transcriptional regulation of mouse and human MMP-9 gene expression in placental trophoblasts.