RT Journal Article
SR Electronic
T1 Activation of p38 Mitogen-Activated Protein Kinase and Activator Protein-1 during the Promotion of Neurite Extension of PC-12 Cells by 15-Deoxy-Δ<sup>12,14</sup>-prostaglandin J<sub>2</sub>
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 607
OP 616
DO 10.1124/mol.63.3.607
VO 63
IS 3
A1 Jung, Kyung Mi
A1 Park, Ki Sook
A1 Oh, Jae Ho
A1 Jung, Soo Youn
A1 Yang, Ki Hwa
A1 Song, Youn Sook
A1 Son, Dong Ju
A1 Park, Young Hyun
A1 Yun, Yeo Pyo
A1 Lee, Myung Koo
A1 Oh, Ki Wan
A1 Hong, Jin Tae
YR 2003
UL http://molpharm.aspetjournals.org/content/63/3/607.abstract
AB 15-Deoxy-Δ12,14-prostaglandin J2(15-deoxy-PGJ2), a naturally occurring ligand, activates the peroxisome proliferator-activated receptor-γ (PPAR-γ). Activation of PPAR-γ has been found to induce cell differentiation in such cells as adipose cells and macrophages. Herein, we investigated whether 15-deoxy-PGJ2 has neuronal cell differentiation and possible underlying molecular mechanisms. Dopaminergic differentiating PC-12 cells treated with 15-deoxy-PGJ2 (0.2 to 1.6 μM) 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-PGJ2 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-PGJ2 (0.8 μM) on NGF-induced neurite extension. This inhibition correlated well with the ability of SB203580 to inhibit the enhancing effect of 15-deoxy-PGJ2on the expression of p38 MAP kinase and activation of AP-1. The promoting ability of 15-deoxy-PGJ2 did not occur through PPAR-γ because synthetic PPAR-γ agonist and antagonist did not change the neurite-promoting effect of 15-deoxy-PGJ2. In addition, contrast to other cells (embryonic midbrain and neuroblastoma SK-N-MC cells), PPAR-γ was not expressed in PC-12 cells. Other structure-related prostaglandins (PGD2 and PGE2) acting via a cell surface G-protein-coupled receptor (GPCR) did not increase basal or NGF-induced neurite extension. Moreover, GPCR (PGE2 and PGD2 receptors) antagonists did not alter the promoting effect of 15-deoxy-PGJ2 on neurite extension and activation of p38 MAP kinase, suggesting that the promoting effect of 15-deoxy-PGJ2 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-PGJ2 on the differentiation of PC-12 cells.