IGF-II-mediated COX-2 gene expression in human keratinocytes through extracellular signal-regulated kinase pathway.
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.
Kim
Hye Jung
HJ
Department of Dermatology, The Catholic University of Korea, Kangnam St Mary's Hospital, 505 Banpo-dong, Seocho-gu, Seoul, South Korea.
Kim
Tae-Yoon
TY
D002455:Cell Division / Q000502:physiology; D002461:Cell Line, Transformed; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D007527:Isoenzymes / Q000235:genetics*; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008565:Membrane Proteins; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism
D007527:Isoenzymes; D008565:Membrane Proteins; D007335:Insulin-Like Growth Factor II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone