Essential role of c-Jun induction and coactivator p300 in epidermal growth factor-induced gene expression of cyclooxygenase-2 in human epidermoid carcinoma A431 cells

Biochim Biophys Acta. 2004 Jul 5;1683(1-3):38-48. doi: 10.1016/j.bbalip.2004.04.003.


Cyclooxygenase-2 (COX-2) is an inducible enzyme responsible for high-level prostaglandin production during inflammation and carcinogenesis. In this study, the transcriptional regulation of COX-2 expression induced by epidermal growth factor (EGF) in human epidermoid carcinoma A431 cells was studied. EGF treatment induced the expression of COX-2 mRNA, protein, promoter and enzyme activity in a time-dependent manner. EGF-induced COX-2 promoter activity was inhibited by overexpression of the dominant-negative forms of Ras and ERK2. Induction of COX-2 and c-Jun by EGF was completely suppressed by MEK inhibitor combined with JNK inhibitor. Analysis of the COX-2 promoter binding proteins by gel mobility shift assay and DNA affinity precipitation assay revealed that c-Jun and p300 binding to CRE/E-box site were responsible for the EGF-induced COX-2 gene transcription. Overexpression of p300 significantly enhanced COX-2 promoter activity in cells overexpressed of c-Jun or treated with EGF. EGF- and c-Jun-induced transcription of COX-2 promoter was repressed by cotransfection of E1A in a dose-dependent manner. All together, these results indicated that the EGF-induced expression of COX-2 in A431 cells was mediated through the Ras-ERK/JNK signaling pathway, and subsequent induction of c-Jun following MAPK activation, in cooperation with coactivator p300, was required for the EGF response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Squamous Cell / enzymology*
  • Carcinoma, Squamous Cell / pathology
  • Cyclooxygenase 2
  • Electrophoretic Mobility Shift Assay
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / pharmacology*
  • Gene Expression
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Isoenzymes / genetics*
  • Isoenzymes / metabolism
  • JNK Mitogen-Activated Protein Kinases*
  • MAP Kinase Kinase 4
  • MAP Kinase Signaling System
  • Membrane Proteins
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Nuclear Proteins / physiology*
  • Promoter Regions, Genetic / genetics
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Proto-Oncogene Proteins c-jun / physiology*
  • Sequence Deletion
  • Trans-Activators / physiology*
  • Transcription, Genetic
  • Tumor Cells, Cultured
  • rac GTP-Binding Proteins / physiology


  • Enzyme Inhibitors
  • Isoenzymes
  • Membrane Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-jun
  • Trans-Activators
  • Epidermal Growth Factor
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • rac GTP-Binding Proteins