Induction of PPARβ and prostacyclin (PGI₂) synthesis by Raf signaling: failure of PGI₂ to activate PPARβ

Abstract

A role for the nuclear receptor peroxisome proliferator‐activated receptor‐β (PPARβ) 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 PPARβ 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 PPARβ and Cox‐2 genes, concomitant with a dramatic increase in PGI2 synthesis. Surprisingly, however, 4‐OHT failed to activate PPARβ transcriptional activity, indicating that PGI2 is insufficient for PPARβ 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 PPARβ. Conversely, inhibition of PGIS blocked PGI2 synthesis but did not affect the AA mediated activation of PPARβ. 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 PPARβ.

15-Hydroxyeicosatetraenoic Acid Is a Preferential Peroxisome Proliferator-Activated Receptor β/δ Agonist

“…This confirms previous findings that AA-derived prostanoids have no detectable effect on the activity of PPAR␤/␦ in human embryonic kidney 293 and NIH3T3 cells (Yu et al, 1995;Forman et al, 1996;Fauti et al, 2006). PGE 2 has been described as an activator of PPAR␤/␦, but this is an indirect effect involving PGE 2 -mediated induction of PI 3 K-AKT signaling and may therefore be dependent on the cell type and experimental system (Wang et al, 2001).…”

“…C and D, fetal lung fibroblasts established from a mouse strain with a floxed Pparb/d allele (Barak et al, 2002) were infected with either the empty retroviral vector (pBabe; left) or a Cre-expressing retrovirus (pBabeCre; right) (Li et al, 1997) mains unclear. The description of PGI 2 (prostacyclin) (Gupta et al, 2000;Hatae et al, 2001) and all-trans retinoic acid (Schug et al, 2007) as PPAR␤/␦ agonists are in conflict with data published by us (Fauti et al, 2006;Rieck et al, 2008) and by others (Yu et al, 1995;Forman et al, 1996;Borland et al, 2008). Unsaturated fatty acids have been reported to interact with the PPAR␤/␦ LBD (Forman et al, 1996;Xu et al, 1999), but their effect on the transcriptional activity of PPAR␤/␦ is weak .…”

“…pCMX-empty has been described previously (Umesono et al, 1991). LexA-PPAR␤/␦, 7L-TATA initiator module (TATAi), and 10ϫGal4SVGL3 have been described previously (Jérô me and Mü ller, 1998;Fauti et al, 2006). LexA-PPAR␣ and LexA-PPAR␥ were constructed in a fashion analogous to the construction of LexA-PPAR␤/␦.…”

“…Prostanoids are major AA metabolites generated by the combined action of cyclooxygenases and prostaglandin or thromboxane synthases. Prostaglandin I 2 (PGI 2 ; prostacyclin) has indeed been postulated to act as a PPAR␤/␦ agonist (Gupta et al, 2000;Hatae et al, 2001), but this issue remains controversial (Yu et al, 1995;Forman et al, 1996;Fauti et al, 2006).…”

Ligand-Mediated Regulation of Peroxisome Proliferator-Activated Receptor (PPAR) β/δ: A Comparative Analysis of PPAR-Selective Agonists and All-trans Retinoic Acid

“…pCMX-empty has been described by Umesono et al (1991). LexA-mPPAR␤, 7L-TATAi, and 10ϫGal4SVGL3 have been described previously (Jérôme and Mü ller, 1998;Fauti et al, 2006). pSG5-hRXRa containing the full-length RXRa cDNA was kindly provided by Dr. A. Baniahmad (Jena, Germany), respectively.…”