title: Activation of p38 mitogen-activated protein kinase and activator protein-1 during the promotion of neurite extension of PC-12 cells by 15-deoxy-delta12,14-prostaglandin J2.
abstract: 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15-deoxy-PGJ(2)), a naturally occurring ligand, activates the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma has been found to induce cell differentiation in such cells as adipose cells and macrophages. Herein, we investigated whether 15-deoxy-PGJ(2) has neuronal cell differentiation and possible underlying molecular mechanisms. Dopaminergic differentiating PC-12 cells treated with 15-deoxy-PGJ(2) (0.2 to 1.6 microM) alone showed measurable neurite extension and expression of neurofilament, a marker of cell differentiation. However, a much greater extent of neurite extension and expression of neurofilament was observed in the presence of NGF (50 ng/ml). In parallel with its increasing effect on the neurite extension and expression of neurofilament, 15-deoxy-PGJ(2) enhanced NGF-induced p38 MAP kinase expression and its phosphorylation in addition to the activation of transcription factor AP-1 in a dose-dependent manner. Moreover, pretreatment of 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(pyridyl)1H-imidazole (SB203580), a specific inhibitor of p38 MAP kinase, inhibited the promoting effect of 15-deoxy-PGJ(2) (0.8 microM) on NGF-induced neurite extension. This inhibition correlated well with the ability of SB203580 to inhibit the enhancing effect of 15-deoxy-PGJ(2) on the expression of p38 MAP kinase and activation of AP-1. The promoting ability of 15-deoxy-PGJ(2) did not occur through PPAR-gamma because synthetic PPAR-gamma agonist and antagonist did not change the neurite-promoting effect of 15-deoxy-PGJ(2). In addition, contrast to other cells (embryonic midbrain and neuroblastoma SK-N-MC cells), PPAR-gamma was not expressed in PC-12 cells. Other structure-related prostaglandins (PGD(2) and PGE(2)) acting via a cell surface G-protein-coupled receptor (GPCR) did not increase basal or NGF-induced neurite extension. Moreover, GPCR (PGE(2) and PGD(2) receptors) antagonists did not alter the promoting effect of 15-deoxy-PGJ(2) on neurite extension and activation of p38 MAP kinase, suggesting that the promoting effect of 15-deoxy-PGJ(2) may not be mediated by GPCR either. These data demonstrate that activation of p38 MAP kinase in conjunction with AP-1 signal pathway may be important in the promoting activity of 15-deoxy-PGJ(2) on the differentiation of PC-12 cells.
authors.affiliation: National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, Korea.
authors.forename: Kyung Mi
authors.initials: KM
authors.lastname: Jung
authors.forename: Ki Sook
authors.initials: KS
authors.lastname: Park
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Oh
authors.forename: Soo Youn
authors.initials: SY
authors.lastname: Jung
authors.forename: Ki Hwa
authors.initials: KH
authors.lastname: Yang
authors.forename: Youn Sook
authors.initials: YS
authors.lastname: Song
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Son
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Park
authors.forename: Yeo Pyo
authors.initials: YP
authors.lastname: Yun
authors.forename: Myung Koo
authors.initials: MK
authors.lastname: Lee
authors.forename: Ki Wan
authors.initials: KW
authors.lastname: Oh
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D004789:Enzyme Activation; D007093:Imidazoles / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000502:physiology; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D016900:Neurofilament Proteins / Q000096:biosynthesis; D009479:Neuropeptides / Q000378:metabolism; D016716:PC12 Cells; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; D007155:Immunologic Factors; D009414:Nerve Growth Factors; D016900:Neurofilament Proteins; D009479:Neuropeptides; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D015230:Prostaglandin D2