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

Citation
K. Subbaramaiah et al., Peroxisome proliferator-activated receptor gamma ligands suppress the transcriptional activation of cyclooxygenase-2 - Evidence for involvement of activator protein-1 and CREB-binding protein/p300, J BIOL CHEM, 276(15), 2001, pp. 12440-12448
Citations number
76
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
276
Issue
15
Year of publication
2001
Pages
12440 - 12448
Database
ISI
SICI code
0021-9258(20010413)276:15<12440:PPRGLS>2.0.ZU;2-7
Abstract
We investigated whether peroxisome proliferator-activated receptor gamma (P PAR gamma) ligands (ciglitazone, troglitazone, and 15-deoxy-Delta (12,14) p rostaglandin J(2)) inhibited cyclooxygenase-2 (COX-2) induction in human ep ithelial cells. Ligands of PPAR gamma inhibited phorbol ester (phorbol 12-m yristate 13-acetate, PMA)-mediated induction of COX-2 and prostaglandin E-2 synthesis. Nuclear run-offs revealed increased rates of COX-2 transcriptio n after treatment with PMA, an effect that was inhibited by PPAR gamma liga nds, PMA-mediated induction of COX-2 promoter activity was inhibited by PPA R gamma ligands; this suppressive effect was prevented by overexpressing a dominant negative form of PPAR gamma or a PPAR response element decoy oligo nucleotide, The stimulatory effects of PMA were mediated by a cyclic AMP re sponse element in the COX-2 promoter. Treatment with PMA increased activato r protein-1 (AP-1) activity and the binding of c-Jun, c-Fos, and ATF-2 to t he cyclic AMP response element, effects that were blocked by PPAR gamma lig ands. These findings raised questions about the mechanism underlying the an ti-AP-1 effect of PPAR gamma ligands. The induction of c-Jun by PMA was blo cked by PPAR gamma ligands. Overexpression of either c-Jun or CREB-binding protein/p300 partially relieved the suppressive effect of PPAR gamma ligand s. When CREB-binding protein and c-Jun were overexpressed together, the abi lity of PPAR gamma ligands to suppress PMA-mediated induction of COX-2 prom oter activity was essentially abrogated. Bisphenol A diglycidyl ether, a co mpound that binds to PPAR gamma but lacks the ability to activate transcrip tion, also inhibited PMA-mediated induction of AP-1 activity and COX-2. Tak en together, these findings are likely to be important for understanding th e anti-inflammatory and anti-cancer properties of PPAR gamma ligands.