Abstract. The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2) is the most recently identified prostaglandin (PG) receptor for both PGD 2 and 15-deoxy-Δ 12,14 -PGJ 2 (15d-PGJ 2 ). We examined the mechanism by which 15d-PGJ 2 enhances nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. CAY10471 (CRTH2 antagonist) inhibited both the neurite-promotion and p38 mitogen-activated protein (MAP) kinase phosphorylation induced by 15d-PGJ 2 . In contrast, 13,14-dihydro-15-keto-PGD 2 (DK-PGD 2 ) (selective CRTH2 agonist) stimulated its phosphorylation but failed to produce neurite-promoting effects. These suggest, for the first time, the action of 15d-PGJ 2 is mediated by CRTH2, although the CRTH2 activation alone is insufficient for the underlying action.
Oxidative stress is thought to play a role in the development of insulin resistance. In order to elucidate the molecular effect of oxidative stress on liver insulin signaling, we analyzed the effect of paraquat (1,1-dimethyl-4,4-dipyridynium; PQ)-derived oxidative stress on the expression of insulin-dependent genes and activation of liver insulin signaling pathway. Incubation of primary cultured rat hepatocytes with 2 mM PQ for 6 h impaired the suppressive effect of insulin on insulin-like growth factor-binding protein-1 (IGFBP-1) gene expression, but did not influence glucose-6-phosphatase gene expression. Insulin-dependent phosphorylation or activation of insulin receptor, insulin receptor substrate-1 and -2, phosphatidylinositol 3-kinase, Akt and forkhead in rhabdomyosarcoma were not affected by PQ pre-treatment. In contrast, PQ treatment impaired insulin-dependent phosphorylation of mammalian target of rapamycin (mTOR). These results indicate that PQ-induced oxidative stress impairs insulin-dependent mTOR activation and that this impairment probably causes inhibition of insulin-dependent repression of IGFBP-1 expression.
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