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
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
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.