Induction of PPARbeta and prostacyclin (PGI2) synthesis by Raf signaling: failure of PGI2 to activate PPARbeta.
A role for the nuclear receptor peroxisome proliferator-activated receptor-beta (PPARbeta) in oncogenesis has been suggested by a number of observations but its precise role remains elusive. Prostaglandin I2 (PGI2, prostacyclin), a major arachidonic acid (AA) derived cyclooxygenase (Cox) product, has been proposed as a PPARbeta 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 PPARbeta and Cox-2 genes, concomitant with a dramatic increase in PGI2 synthesis. Surprisingly, however, 4-OHT failed to activate PPARbeta transcriptional activity, indicating that PGI2 is insufficient for PPARbeta activation. In agreement with this conclusion, the overexpression of ectopic Cox-2 and PGI2 synthase (PGIS) resulted in massive PGI2 synthesis but did not activate the transcriptional activity of PPARbeta. Conversely, inhibition of PGIS blocked PGI2 synthesis but did not affect the AA mediated activation of PPARbeta. Our data obtained with four different cell types and different experimental strategies do not support the prevailing opinion that PGI2 plays a significant role in the regulation of PPARbeta.
Fauti
Tanja
T
Institute of Molecular Biology and Tumor Research (IMT), Philipps-University, Marburg, Germany.
Müller-Brüsselbach
Sabine
S
Kreutzer
Mihaela
M
Rieck
Markus
M
Meissner
Wolfgang
W
Rapp
Ulf
U
Schweer
Horst
H
Kömhoff
Martin
M
Müller
Rolf
R
D000818:Animals; D019898:Autocrine Communication; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases; D011453:Prostaglandins / Q000096:biosynthesis / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection
D008565:Membrane Proteins; D048068:PPAR-beta; D011453:Prostaglandins; D013629:Tamoxifen; C016601:afimoxifene; D011464:Epoprostenol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone