Regulation of BiP gene expression by cyclopentenone prostaglandins through unfolded protein response element

Delta12-Prostaglandin (PG) J2, a cyclopentenone prostaglandin, plays a role in various stress responses. BiP, a stress-inducible chaperone protein, is implicated in protein folding and translocation in endoplasmic reticulum and induced in the condition of accumulation of unfolded proteins. Here, we examined the effect of Delta12-PGJ2 on the expression of the BiP gene. Delta12-PGJ2 markedly stimulated the expression of the BiP gene in a time- and concentration-dependent manner in HeLa cells. This stimulation was specific for cyclopentenone PGs among various PGs. Cycloheximide pretreatment completely inhibited the Delta12-PGJ2-induced expression of the BiP gene, suggesting that the effects on nascent protein synthesis are involved in the signaling mechanism. Delta12-PGJ2 markedly stimulated the promoter activity of the 5'-flanking region of the BiP gene through the unfolded protein response element. Furthermore, Delta12-PGJ2 stimulated the enhancer activity of the 3'-half of the unfolded protein response element, and this stimulation required three nucleotides within this region. Gel mobility shift assay demonstrated that this region was occupied with two specific nuclear protein factors with different mobilities in the control cells, and Delta12-PGJ2 induced the dissociation of the protein-DNA complex with lower mobility. These findings indicate that Delta12-PGJ2 stimulates the expression of BiP gene through the 3'-half of the unfolded protein response element.