Induction of PPAR beta and prostacyclin (PGI sub(2)) synthesis by Raf signaling: failure of PGI sub(2) to activate PPAR beta

A role for the nuclear receptor peroxisome proliferator-activated receptor- beta (PPAR beta ) in oncogenesis has been suggested by a number of observations but its precise role remains elusive. Prostaglandin I sub(2) (PGI sub(2), prostacyclin), a major arachidonic acid (AA) derived cyclooxygenase (Cox) product, has been proposed as a PPAR beta agonist. Here, we show that the 4-hydroxytamoxifen (4-OHT) mediated activation of a C-Raf-estrogen receptor fusion protein leads to the induction of both the PPAR beta and Cox-2 genes, concomitant with a dramatic increase in PGI sub(2) synthesis. Surprisingly, however, 4-OHT failed to activate PPAR beta transcriptional activity, indicating that PGI sub(2) is insufficient for PPAR beta activation. In agreement with this conclusion, the overexpression of ectopic Cox-2 and PGI sub(2) synthase (PGIS) resulted in massive PGI sub(2) synthesis but did not activate the transcriptional activity of PPAR beta . Conversely, inhibition of PGIS blocked PGI sub(2) synthesis but did not affect the AA mediated activation of PPAR beta . Our data obtained with four different cell types and different experimental strategies do not support the prevailing opinion that PGI sub(2) plays a significant role in the regulation of PPAR beta .