title: Induction of PPARbeta and prostacyclin (PGI2) synthesis by Raf signaling: failure of PGI2 to activate PPARbeta.
abstract: 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.
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps-University, Marburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Fauti
authors.forename: Sabine
authors.initials: S
authors.lastname: Müller-Brüsselbach
authors.forename: Mihaela
authors.initials: M
authors.lastname: Kreutzer
authors.forename: Markus
authors.initials: M
authors.lastname: Rieck
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Meissner
authors.forename: Ulf
authors.initials: U
authors.lastname: Rapp
authors.forename: Horst
authors.initials: H
authors.lastname: Schweer
authors.forename: Martin
authors.initials: M
authors.lastname: Kömhoff
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
mesh_terms: 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
chemical_list: 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