Fibroblast growth factor-1 induced promatrilysin expression through the activation of extracellular-regulated kinases and STAT3
Fibroblast growth factor-1 induced promatrilysin expression through the activation of extracellular-regulated kinases and STAT3
复制标题
DOI：
10.1038/sj.neo.7900207
复制
发表时间：
2002-01-01
期刊：
影响因子：
4.8
通讯作者：
Bowden, GT
中科院分区：
文献类型：
--
作者：
Udayakumar, TS;Stratton, MS;Bowden, GT
MMP，基质溶解素（MMP-7）已显示在前列腺癌细胞中过表达并增加前列腺癌细胞侵袭。前列腺基质成纤维细胞分泌一种或多种因子，包括诱导LNCaP细胞中基质溶素原表达的成纤维细胞生长因子-1（FGF-1）。在本研究中，我们调查的信号转导通路参与FGF-1诱导的前基质溶素的表达。FGF-1处理显著增加了细胞外信号调节激酶1和2（ERK 1和ERK 2）的活化。这种诱导具有时间依赖性，并持续至给药后24小时。用MEK 1/2抑制剂（PD 98059）处理细胞完全消除了ERK活化，并阻断了FGF-1介导的前基质溶解素表达的诱导。用人基质溶解素启动子的瞬时转染研究导致报告荧光素酶活性增加4 - 5倍，该活性被MEK 1/2抑制剂（PD 98059）阻断。在FGF-1处理和用20 μ M PD 98059预处理后观察到信号转导子和转录激活子3（STAT 3）的丝氨酸磷酸化-消除了STAT 3磷酸化。瞬时转染显性负性STAT 3抑制FGF-1诱导的基质溶素启动子的反式激活，表明STAT 3在FGF-1诱导的基质溶素表达中起重要作用。我们提出，FGF-1诱导的信号通路，导致promatrilysin的表达是ERK依赖性的，并导致磷酸化的Ser-727的STAT 3，磷酸化的STAT 3，然后结合和反式激活matrilysin启动子。我们的研究结果表明，ERK-MAP激酶和转录因子STAT 3是FGF-1介导的信号传导的重要组成部分，其诱导LNCaP细胞中的前基质溶解素表达。
The MMP, matrilysin (MMP-7) has been shown to be overexpressed in prostate cancer cells and to increase prostate cancer cell invasion. Prostate stromal fibroblasts secrete factor(s), including fibroblast growth factor-1 (FGF-1) that induces promatrilysin expression in LNCaP cells. In the present study, we investigated the signal transduction pathway involved in the FGF-1-induced expression of promatrilysin. FGF-1 treatment significantly increased the activation of extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2). This induction was time-dependent and was sustained until 24 hours after treatment. Treating the cells with MEK1/2 inhibitor (PD98059) eliminated ERK activation completely and blocked FGF-1-mediated induction of promatrilysin expression. Transient transfection studies with human matrilysin promoter resulted in a four- to five-fold increase in reporter luciferase enzyme activity that was blocked by the MEK1/2 inhibitor (PD98059). Serine phosphorylation of signal transducer and activator of transcription 3 (STAT3) was observed after FGF-1 treatment and pretreatment with 20 muM PD98059-abolished STAT3 phosphorylation. Transient transfection with dominant negative STAT3 inhibited FGF-1-induced transactivation of the matrilysin promoter indicating that STAT3 plays an important role in FGF-1-induced matrilysin expression. We propose that the FGF-1-induced signaling pathway that leads to promatrilysin expression is ERK-dependent and leads to phosphorylation of Ser-727 on STAT3, phosphorylated STAT3, then binds and transactivates the matrilysin promoter. Our results demonstrate that ERK-MAP kinase and transcription factor STAT3 are important components of FGF-1-mediated signaling, which induce promatrilysin expression in LNCaP cells.