Peroxisome proliferator-activated receptor γ ligands suppress the transcriptional activation of cyclooxygenase-2. Evidence for involvement of activator protein-1 and CREB-binding protein/p300

Kotha Subbaramaiah, Derrick T. Lin, Janice C. Hart, Andrew J. Dannenberg

Research output: Contribution to journalArticle

270 Scopus citations

Abstract

We investigated whether peroxisome proliferator-activated receptor γ (PPARγ) ligands (ciglitazone, troglitazone, and 15-deoxy-Δ 12,14 prostaglandin J2) inhibited cyclooxygenase-2 (COX-2) induction in human epithelial cells. Ligands of PPARγ inhibited phorbol ester (phorbol 12-myristate 13-acetate, PMA)-mediated induction of COX-2 and prostaglandin E2 synthesis. Nuclear run-offs revealed increased rates of COX-2 transcription after treatment with PMA, an effect that was inhibited by PPARγ ligands. PMA-mediated induction of COX-2 promoter activity was inhibited by PPARγ ligands; this suppressive effect was prevented by overexpressing a dominant negative form of PPARγ or a PPAR response element decoy oligonucleotide. The stimulatory effects of PMA were mediated by a cyclic AMP response element in the COX-2 promoter. Treatment with PMA increased activator protein-1 (AP-1) activity and the binding of c-Jun, c-Fos, and ATF-2 to the cyclic AMP response element, effects that were blocked by PPARγ ligands. These findings raised questions about the mechanism underlying the anti-AP-1 effect of PPARγ ligands. The induction of c-Jun by PMA was blocked by PPARγ ligands. Overexpression of either c-Jun or CREB-binding protein/p300 partially relieved the suppressive effect of PPARγ ligands. When CREB-binding protein and c-Jun were overexpressed together, the ability of PPARγ ligands to suppress PMA-mediated induction of COX-2 promoter activity was essentially abrogated. Bisphenol A diglycidyl ether, a compound that binds to PPARγ but lacks the ability to activate transcription, also inhibited PMA-mediated induction of AP-1 activity and COX-2. Taken together, these findings are likely to be important for understanding the anti-inflammatory and anti-cancer properties of PPARγ ligands.

Original languageEnglish (US)
Pages (from-to)12440-12448
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number15
DOIs
StatePublished - Apr 13 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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