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^12,14-prostaglandin J₂

Abstract

15-Deoxy-⌬12,14 -prostaglandin J 2 (15-deoxy-PGJ 2 ), a naturally occurring ligand, activates the peroxisome proliferator-activated receptor-␥ (PPAR-␥). Activation of PPAR-␥ 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 M) 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 M) 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-␥ because synthetic PPAR-␥ 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-␥ 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

Differential Effects of Myocilin and Optineurin, Two Glaucoma Genes, on Neurite Outgrowth

“…49,50 15-Deoxy-PGJ2, a metabolite of prostaglandin D2 and a ligand of peroxisome proliferatorsactivated receptor-␥, is known to induce neurite outgrowth in PC12 cells via activation of p38MAP kinase in conjunction with the AP-1 signal pathway. 51,52 Regulation of dynamics of actin filament by agents such as jasplakinolide that induce actin polymerization by enhancing actin filament nucleation 53 has also been shown to be crucial for neurite outgrowth. 54 In our hands, addition of forskolin but none of the other agents attenuated the inhibitory effect by myocilin overexpression on neurite outgrowth ( Figure 6).…”

Inhibition of Activator Protein 1 Activation, Vascular Endothelial Growth Factor, and Cyclooxygenase-2 Expression by 15-Deoxy-Δ12,14-Prostaglandin J2 in Colon Carcinoma Cells: Evidence for a Redox-Sensitive Peroxisome Proliferator-Activated Receptor-γ-Independent Mechanism

“…JNK activity also is regulated by phosphorylation by various upstream MAPK kinases (46). Positive and negative effects of 15d-PGJ 2 on ERK, JNK, and p38 MAPK activities have been reported (37,(47)(48)(49)(50). These effects result in the regulation of the level of phosphorylation and activation of AP-1 components.…”

15d-Prostaglandin J2 Enhancement of Nerve Growth Factor–Induced Neurite Outgrowth Is Blocked by the Chemoattractant Receptor– Homologous Molecule Expressed on T-Helper Type 2 Cells (CRTH2) Antagonist CAY10471 in PC12 Cells

“…15d-PGJ 2 has been shown to exert its effect through the activation of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR γ ) (1,4) and the classical PGD 2 receptor (DP) (5). However, in PC12 cells, neither PPAR γ antagonist nor DP antagonist have been shown to affect the 15d-PGJ 2 enhancement of NGF-induced neurite outgrowth (3). Therefore, the mechanism by which 15d-PGJ 2 activates NGF-induced neurite outgrowth is unknown.…”

“…Jung et al demonstrated that in PC12 cells, the 15d-PGJ 2 enhancement of NGF-induced neurite outgrowth depends on activation of p38 MAP kinase and not activations of PPAR γ , DP, or PGE 2 receptor, which suggests that the promoting effect of 15d-PGJ 2 may not be mediated by cell surface G-protein-coupled receptors (3). Here, we demonstrated that the CRTH2 antagonist CAY10471 can inhibit both the promoting effect of 15d-PGJ 2 on NGF-induced neurite outgrowth and 15d-PGJ 2 -induced phosphorylation of p38 MAP kinase.…”

“…12,14 -prostaglandin (PG) J 2 (15d-PGJ 2 ), a cyclopentane metabolite of PGD 2 , displays multiple cellular functions (1 -4), including the promotion of nerve growth factor (NGF)-induced neurite outgrowth in pheochromocytoma PC12 cells (2,3). 15d-PGJ 2 has been shown to exert its effect through the activation of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR γ ) (1,4) and the classical PGD 2 receptor (DP) (5).…”