COX-2 promoter activation by AT1R-Gq-PAK-p38beta signaling in intestinal epithelial cells

Biochim Biophys Acta. Jun-Jul 2008;1779(6-7):408-13. doi: 10.1016/j.bbagrm.2008.05.004. Epub 2008 May 13.

Abstract

Cyclooxygenase-2 (COX-2) is rapidly induced by angiotensin (Ang)-II in the non-tumorigenic, rat intestinal epithelial cell line, IEC-18, through its G-protein coupled receptor, AT1R. Here, we investigate the ability of Ang II to regulate transcription of the COX-2 promoter and a Gal4-CREB heterologous promoter in IEC-18 cells. Ang II and EGF induced similar levels of transcription from the COX-2 and Gal4-CREB promoters. Over-expression of constitutively active Galpha proteins q, 11, 12 and 13, showed induction by GalphaqQ209L and by Galpha11Q209L for both the COX-2 and Gal4-CREB promoters. Co-expression of RGS 2, 3 or 4 but not the RGS domain of p115RhoGEF inhibited Ang II-dependent induction of the COX-2 and Gal4-CREB promoters. Expression of constitutively active MKK6 EE but not MKK3 EE induced the COX-2 and Gal4-CREB promoters via p38MAPK. SB202190 but not PD98059 inhibited induction of the COX-2 promoter by over-expression of the constitutively active PAK1T423E. Expression of the kinase-inactive PAK1K299R inhibited both Ang II-dependent induction of the COX-2 promoter and induction of the COX-2 and Gal4-CREB promoters by GalphaqQ209L. These data demonstrate that in IEC-18 cells, Ang II-dependent activation of the COX-2 promoter is mediated primarily through Gq/11 signaling via a PAK/MKK6/p38beta/CREB signaling cascade.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin II / pharmacology
  • Animals
  • Cell Line
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclooxygenase 2 / genetics*
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / metabolism
  • Flavonoids / pharmacology
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Imidazoles / pharmacology
  • Intestinal Mucosa / metabolism*
  • Intestines / cytology
  • MAP Kinase Kinase 6 / metabolism
  • MAP Kinase Signaling System / drug effects
  • Mitogen-Activated Protein Kinase 11 / metabolism*
  • Promoter Regions, Genetic*
  • Pyridines / pharmacology
  • Rats
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Signal Transduction / drug effects
  • p21-Activated Kinases / metabolism*

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Pyridines
  • Receptor, Angiotensin, Type 1
  • Angiotensin II
  • Cyclooxygenase 2
  • Ptgs2 protein, rat
  • Pak1 protein, rat
  • p21-Activated Kinases
  • Mitogen-Activated Protein Kinase 11
  • MAP Kinase Kinase 6
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one