Jun N-terminal kinase 1 mediates transcriptional induction of matrix metalloproteinase 9 expression
Jun N-terminal kinase 1 mediates transcriptional induction of matrix metalloproteinase 9 expression
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DOI：
10.1038/sj.neo.7900135
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发表时间：
2001-01-01
期刊：
影响因子：
4.8
通讯作者：
Shemirani, B
中科院分区：
文献类型：
--
作者：
Crowe, DL;Tsang, KJ;Shemirani, B
肿瘤细胞的侵袭和转移需要与细胞外基质（ECM）的粘附及其组分的受控降解的精确协调。侵袭性细胞分泌称为基质金属蛋白酶（MMPs）的蛋白水解酶，其降解特定的基底膜分子。这些酶的表达受多种信号传导机制调节，包括促分裂原活化蛋白激酶（MAPK）途径。该信号级联的终端效应物之一是jun N-末端激酶1（JNK 1），其磷酸化转录因子c-jun，其是AP-1复合物的组分。MMP-9的表达受该基因启动子中两个特征性的AP-1位点的调控。为了确定JNK 1活性如何调节MMP-9在人鳞状细胞癌细胞系中的表达，我们在SCC 25细胞中过表达该激酶。JNK 1过表达诱导MMP-9蛋白水平和活性在这个细胞系。MMP-9表达升高与JNK 1过表达克隆对重建基底膜的侵袭增加相关。MMP-9启动子的定点突变显示，JNK 1与其转录因子靶点c-jun通过近端AP-Ⅰ位点在转录水平上协同增加MMP-9的表达。这些结果表明，JNK 1的表达升高可能有助于增加MMP-9活性和肿瘤细胞的ECM侵袭。
Tumor cell invasion and metastasis require precise coordination of adherence to extracellular matrix (ECM) and controlled degradation of its components. Invasive cells secrete proteolytic enzymes known as matrix metalloproteinases (MMPs) which degrade specific basement membrane molecules. Expression of these enzymes is regulated by multiple signaling mechanisms, including the mitogen-activated protein kinase (MAPK) pathway. One of the terminal effecters of this signaling cascade is jun N-terminal kinase 1 (JNK1) which phosphorylates the transcription factor c-jun, a component of the AP-1 complex. MMP-9 expression is regulated by two well-characterized AP-I sites in the promoter of this gene. To determine how JNK1 activity regulated MMP-9 expression in human squamous cell carcinoma lines, we overexpressed this kinase in SCC25 cells. JNK1 overexpression induced MMP-9 protein levels and activity in this cell line. Elevated MMP-9 expression correlated with increased invasion of reconstituted basement membranes by JNK1-overexpressing clones. Site-directed mutagenesis of the MMP-9 promoter revealed that JNK1 cooperated with its transcription factor target c-jun to increase MMP-9 expression at the transcriptional level via the proximal AP-I site. These results suggest that elevated JNK1 expression may contribute to increased MMP-9 activity and ECM invasion by tumor cells.