GATA3 inhibits GCM1 activity and trophoblast cell invasion.
GATA3 inhibits GCM1 activity and trophoblast cell invasion.
复制标题
GATA3抑制GCM1活性和滋养细胞侵袭。
DOI：
10.1038/srep21630
复制
发表时间：
2016-02-22
影响因子：
4.6
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Chiu YH;Chen H
人类胎盘的发育涉及滋养层细胞从锚定绒毛侵入母体蜕膜。胎盘转录因子GCM1通过转录激活HtrA4基因来调节滋养层细胞的侵袭，HtrA4基因编码一种丝氨酸蛋白酶。GATA3转录因子调控滋养层细胞分化，在侵袭性小鼠滋养层巨细胞中高表达。GCM1对滋养细胞侵袭的调节可能涉及新的细胞因子。在这里，我们发现GATA3与GCM1相互作用，并抑制其抑制滋养层侵袭的活性。免疫组织化学结果表明，GATA3和GCM1在人胎盘绒毛细胞滋养层、合体滋养层和绒毛外滋养层细胞中共表达。有趣的是，GATA3通过GCM1的DNA结合结构域和第一转录激活结构域以及GATA3的转录激活结构域和锌指1结构域与GCM1相互作用，而不是GCM2同系物。虽然GATA3不影响GCM1的DNA结合活性，但它抑制了GCM1的转录活性，从而抑制了HtrA4启动子的活性。相应地，GATA3基因敲除上调了BeWo和JEG-3滋养层细胞HtrA4的表达，并增强了这两种细胞的侵袭活性。这项研究揭示了胎盘中一种新的GATA3功能，它是GCM1活性和滋养层侵袭的负调控因子。
Development of human placenta involves the invasion of trophoblast cells from anchoring villi into the maternal decidua. Placental transcription factor GCM1 regulates trophoblast cell invasion via transcriptional activation of HtrA4 gene, which encodes a serine protease enzyme. The GATA3 transcription factor regulates trophoblast cell differentiation and is highly expressed in invasive murine trophoblast giant cells. The regulation of trophoblastic invasion by GCM1 may involve novel cellular factors. Here we show that GATA3 interacts with GCM1 and inhibits its activity to suppress trophoblastic invasion. Immunohistochemistry demonstrates that GATA3 and GCM1 are coexpressed in villous cytotrophoblast cells, syncytiotrophoblast layer, and extravillous trophoblast cells of human placenta. Interestingly, GATA3 interacts with GCM1, but not the GCM2 homologue, through the DNA-binding domain and first transcriptional activation domain in GCM1 and the transcriptional activation domains and zinc finger 1 domain in GATA3. While GATA3 did not affect DNA-binding activity of GCM1, it suppressed transcriptional activity of GCM1 and therefore HtrA4 promoter activity. Correspondingly, GATA3 knockdown elevated HtrA4 expression in BeWo and JEG-3 trophoblast cell lines and enhanced the invasion activities of both lines. This study uncovered a new GATA3 function in placenta as a negative regulator of GCM1 activity and trophoblastic invasion.