Activation of heat shock transcription factors by delta 12-prostaglandin J2 and its inhibition by intracellular glutathione.
We recently showed that delta 12-prostaglandin (PG) J2 bound to the thiol groups of nuclear proteins and stimulated the synthesis of a 67-kDa heat shock protein (HSP) in porcine aortic endothelial cells, and that intracellular glutathione (GSH) blocked this binding and HSP induction (Koizumi et al., Biochem Pharmacol 44: 1597-1602, 1992). In the present study, we examined the molecular mechanism underlying the induction of HSP by delta 12-PGJ2. Treatment of cells with delta 12-PGJ2 induced the activation of heat shock transcription factors (HSF) in a time- and concentration-dependent manner. Cycloheximide pretreatment inhibited this activation. Treatment of cells with buthionine sulfoximine, an inhibitor of GSH synthesis, depleted the intracellular GSH and enhanced the activation of HSF by delta 12-PGJ2, but treatment with GSH increased the intracellular GSH level and thus reduced the activation. Moreover, the thiol-reactive agents arsenite and diethylmaleate also induced the activation of HSF, and this activation was inhibited by GSH treatment and enhanced by buthionine sulfoximine treatment. These results taken together suggest that delta 12-PGJ2 binds to the thiol groups of nuclear proteins and activates HSF, leading to the synthesis of the 67-kDa HSP.
Koizumi
T
T
Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Negishi
M
M
Ichikawa
A
A
D000818:Animals; D001483:Base Sequence; D019328:Buthionine Sulfoximine; D002460:Cell Line / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D005978:Glutathione / Q000032:analysis / Q000494:pharmacology*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D008969:Molecular Sequence Data; D015230:Prostaglandin D2 / Q000737:chemistry / Q000494:pharmacology* / Q000031:analogs & derivatives; D014176:Protein Biosynthesis; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013552:Swine; D014157:Transcription Factors
D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D013438:Sulfhydryl Compounds; D014157:Transcription Factors; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; C040810:9-deoxy-9,10-didehydro-12,13-didehydro-13,14-dihydroprostaglandin D2; D004247:DNA; D005978:Glutathione; D015230:Prostaglandin D2