IGF-II-mediated COX-2 gene expression in human keratinocytes through extracellular signal-regulated kinase pathway
IGF-II-mediated COX-2 gene expression in human keratinocytes through extracellular signal-regulated kinase pathway
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DOI：
10.1111/j.0022-202x.2004.23317.x
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发表时间：
2004-09-01
影响因子：
6.5
通讯作者：
Kim, TY
中科院分区：
文献类型：
--
作者：
Kim, HJ;Kim, TY
我们监测了胰岛素样生长因子-II（IGF-II）处理的人角质形成细胞中环氧合酶-2（考克斯-2）的表达，并探讨了与考克斯-2表达相关的IGF-II信号通路。IGF-II可诱导考克斯-2 mRNA和蛋白水平的表达，而酪氨酸激酶、Src和PI 3-激酶抑制剂可抑制IGF-II对考克斯-2表达的上调。细胞外信号调节激酶（ERK）和c-Jun N-末端激酶（JNK）1的抑制也降低了IGF-II引起的考克斯-2表达的增加，但p38的抑制没有降低。为了进一步研究这些丝裂原活化蛋白激酶（MAPK）在IGF-II诱导的考克斯-2表达中的作用，我们使用显性阴性质粒MEK 1（DN-MEK 1）、p38（DN-p38）和JNK 1（DN-JNK 1）进行了考克斯-2启动子分析。虽然IGF-II使考克斯-2启动子活性增加约2.5倍，但这种增加可被DN-MEK 1或DN-JNK 1共转染阻断。然而，DN-p38不能阻断IGF-II诱导的考克斯-2启动子活性。此外，ERK或JNK 1的抑制降低了IGF-II诱导的前列腺素E-2合成或细胞增殖的增加。这些结果表明，IGF-II通过酪氨酸激酶-Src-ERK和酪氨酸激酶-PI 3-激酶途径诱导考克斯-2表达，而不是通过p38 MAPK途径，并且IGF-II上调考克斯-2也需要基础JNK活性。
We monitored cyclooxygenase-2 (COX-2) expression in the insulin-like growth factor-II (IGF-II) treated human keratinocytes and explored the IGF-II signaling pathways with respect to the expression of COX-2. IGF-II induced COX-2 mRNA and protein levels, and the up-regulation of COX-2 expression by IGF-II was reduced by pretreatment with inhibitors of tyrosine kinase, Src and PI3-kinase. The inhibition of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) 1 also reduced the increased expression of COX-2 by IGF-II, but the inhibition of p38 did not. To further examine the roles of these mitogen-activated protein kinases (MAPKs) in IGF-II-induced COX-2 expression, we performed COX-2 promoter analysis using dominant negative plasmids of MEK1 (DN-MEK1), p38 (DN-p38) and JNK1 (DN-JNK1). Although IGF-II increased COX-2 promoter activity approximately 2.5-fold, this increase was blocked by cotransfection with DN-MEK1 or DN-JNK1. However, DN-p38 did not block the IGF-II-induced COX-2 promoter activity. In addition, inhibition of ERK or JNK1 reduced the increase of IGF-II-induced prostaglandin E-2 synthesis or cell proliferation. These results suggest that IGF-II induces COX-2 expression through the tyrosine kinase-Src-ERK and tyrosine kinase-PI3-kinase pathways, but not via p38 MAPK pathway, and that the basal JNK activity is required for the upregulation of COX-2 by IGF-II, as well.