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 Journal Article
| Authors: | Subbaramaiah, K.; Lin, D. T.; Hart, J. C.; Dannenberg, A. J. |
| Article Title: | 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 |
| 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. |
| Keywords: | controlled study; human cell; promoter region; genetics; protein function; neoplasm; neoplasms; proteins; metabolism; gene overexpression; nuclear protein; stress activated protein kinase; transcription initiation; cell line; protein binding; membrane proteins; transcription factor; antineoplastic activity; transcription factors; nuclear proteins; biosynthesis; transcription regulation; cyclooxygenase 2; arthritis; nucleotide sequence; transactivator protein; prostaglandin e2; ptgs2 protein, human; membrane protein; ligand; transactivation; ligands; base sequence; trans-activators; antiinflammatory activity; dna primers; primer dna; biochemistry; isoenzymes; esters; enzyme induction; gene activity; receptors, cytoplasmic and nuclear; phorbol 13 acetate 12 myristate; tetradecanoylphorbol acetate; cells; prostaglandin synthesis; dinoprostone; isoenzyme; transcription factor ap 1; cell receptor; protein c fos; promoter regions (genetics); trans-activation (genetics); transcription factor ap-1; creb-binding protein; prostaglandin synthase; prostaglandin-endoperoxide synthases; cyclic amp responsive element binding protein binding protein; promoter activity; troglitazone; peroxisome proliferator activated receptor agonist; humans; human; priority journal; article; cyclic amp responsive element; 15 deoxy delta12,14 prostaglandin j2; ciglitazone; crebbp protein, human |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 276 |
| Issue: | 15 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2001-04-13 |
| Start Page: | 12440 |
| End Page: | 12448 |
| Language: | English |
| DOI: | 10.1074/jbc.M007237200 |
| PUBMED: | 11278336 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
