IGF-II-mediated COX-2 gene expression in human keratinocytes through extracellular signal-regulated kinase pathway

J Invest Dermatol. 2004 Sep;123(3):547-55. doi: 10.1111/j.0022-202X.2004.23317.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Division / physiology
  • Cell Line, Transformed
  • Cyclooxygenase 2
  • Dinoprostone / biosynthesis
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology
  • Humans
  • Insulin-Like Growth Factor II / pharmacology*
  • Isoenzymes / genetics*
  • Keratinocytes / cytology
  • Keratinocytes / physiology*
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / physiology
  • Membrane Proteins
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Promoter Regions, Genetic
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Protein-Tyrosine Kinases / metabolism
  • Up-Regulation
  • src-Family Kinases / metabolism


  • Isoenzymes
  • Membrane Proteins
  • Insulin-Like Growth Factor II
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • src-Family Kinases
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases
  • Dinoprostone