15-deoxy-delta12,14 prostaglandin J2 synergizes with phorbol ester to induce proliferation in Swiss 3T3 cells independently of peroxisome proliferator-activated receptor gamma and PGD2 receptors.
15-deoxy-Delta(12,14) prostaglandin J(2) (15dPGJ(2)), a peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, induced synergistic stimulation of DNA synthesis in the presence of phorbol dibutyrate (PDB) in Swiss 3T3 cells. This effect was dose-dependent and the maximum response was obtained at 2 microM 15dPGJ(2), although higher concentrations of 15dPGJ(2) were cytotoxic. Furthermore, 15dPGJ(2) synergizes with PDB to induce cell-cycle progression and cyclin D(1) expression. Rosiglitazone and ciglitazone, two other agonists of PPARgamma, did not synergize with PDB to induce DNA synthesis, suggesting that activation of PPARgamma is not involved in 15dPGJ(2)-induced DNA synthesis. 15dPGJ(2) neither increased the levels of cAMP, nor changed the phosphorylation state of CREB, nor induced calcium mobilization, indicating that 15dPGJ(2) effects are independent of prostaglandin D(2) receptor (DP1 and DP2). Moreover, 15dPGJ(2) did not induce activation of PKB/AKT or activation of extracellular signal-regulated kinase (ERK). These results establish a proliferative role for 15dPGJ(2) in Swiss 3T3 cells independent of the activation of PPARgamma or the PGD(2) receptors.
Castaño
E
E
Departament de Ciencies Fisiològiques II, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
Gil
J
J
D016475:3T3 Cells; D000818:Animals; D002118:Calcium / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D004357:Drug Synergism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D008934:Mitogens; D010703:Phorbol Esters; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D014157:Transcription Factors; D004247:DNA; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D015230:Prostaglandin D2; D002118:Calcium; C036293:prostaglandin D2 receptor