Abstract
Although previous reports have examined the function of prostaglandin E₂ (PGE₂) on gap junctions and undifferentiated stem cells, its effects on the reciprocal action of connexin (Cx) isoforms and undifferentiation in embryonic stem cells (ESCs) are unclear. Therefore, we investigated the role of PGE₂ on Cx isoforms and maintenance of mouse ESC undifferentiated state. We have analysed 10 Cx genes, but found nine of them. PGE₂ (50 μM) stimulated Cx31, Cx32, Cx40, Cx43 and Cx45 mRNA expression. Amongst them, PGE₂ maximally stimulated the Cx43 mRNA expression and gap junction inter-cellular coupling. Therefore, we investigated the effect of PGE₂ on Cx43 expression. PGE₂ activated cAMP/protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K)/Akt phosphorylation. In addition, treatments of adenylate cyclase activators increased Cx43 expression, but not PI3K/Akt phosphorylation. PGE₂ also inactivated GSK-3β and stimulated active-β-catenin. Furthermore, a ChiP assay demonstrated the association of β-catenin with the Cx26 (as control) and Cx43 promoter. Finally, down-regulation of PGE₂-induced Cx isoforms by AH 6809, Cx31-, Cx43-, Cx45 small interfering (si)RNA and 18α-glycyrrhetinic acid decreased levels of undifferentiated markers of ESCs, including Oct4, FoxD3, Sox2 and SSEA-1, but Nanog did not be down-regulated by Cx43 siRNA. PGE₂ stimulates Cx isoforms via GSK-3β/β-catenin via EP2-receptor-dependent cAMP/PKA and PI3K/Akt in mouse ESCs, thereby partially contributing to the maintenance of their undifferentiated state.
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