Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor
Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor
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DOI：
10.1242/jcs.02465
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发表时间：
2005-08-01
影响因子：
4
通讯作者：
Fabra, A
中科院分区：
文献类型：
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作者：
Jordà, M;Olmeda, D;Fabra, A
在上皮MDCK细胞中，转录因子Snail的过度表达促进了上皮-间质转化（EMT）和侵袭性表型的获得。我们在这里报道，Snail的表达与基质金属蛋白酶MMP-9的启动子活性和表达的增加有关。蜗牛沉默对MMP-9表达的影响证实了这一发现。蜗牛诱导MMP-9的转录是由依赖于MAPK和磷酸肌苷激酶（PI3K）信号通路的机制驱动的。虽然启动子的其他区域需要蜗牛完全刺激，但最小片段（核苷酸-97至+114）在Sp-1磷酸化增加以及Sp-1或Ets-1与该区域所含的GC-box元件结合后产生响应。MEK显性阴性形式的表达减少了这些复合物。在蜗牛表达的细胞中，还观察到核因子κ B （NF κ B）与MMP-9启动子上游区域（核苷酸-562）的结合适度增加。有趣的是，致癌基因H-Ras （RasV12）与Snail协同诱导MMP-9的转录和表达。总之，这些结果表明MMP-9转录在蜗牛表达的反应中被激活，并且它可能至少部分地解释了蜗牛表达细胞的侵袭性。
Overexpression of the transcription factor Snail in epithelial MDCK cells promotes the epithelial-mesenchymal transition (EMT) and the acquisition of an invasive phenotype. We report here that the expression of Snail is associated with an increase in the promoter activity and expression of the matrix metalloproteinase MMP-9. The effect of Snail silencing on MMP-9 expression corroborates this finding. Induced transcription of MMP-9 by Snail is driven by a mechanism dependent on the MAPK and phosphoinositide 3-kinase (PI3K) signalling pathways. Although other regions of the promoter were required for a complete stimulation by Snail, a minimal fragment (nucleotides -97 to +114) produces a response following an increased phosphorylation of Sp-1 and either Sp-1 or Ets-1 binding to the GC-box elements contained in this region. The expression of a dominant negative form of MEK decreased these complexes. A moderate increase in the binding of the nuclear factor kappa B (NF kappa B) to the upstream region (nucleotide -562) of the MMP-9 promoter was also observed in Snail-expressing cells. Interestingly, oncogenic H-Ras (RasV12) synergistically co-operates with Snail in the induction of MMP-9 transcription and expression. Altogether, these results indicate that MMP-9 transcription is activated in response to Snail expression and that it might explain, at least in part, the invasive properties of the Snail-expressing cells.