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Molecular Basis for the Direct Inhibition of AP-1 DNA Binding by 15-Deoxy-Δ12,14-prostaglandin J2

AutorPérez-Sala, Dolores ; Cernuda-Morollón, Eva; Cañada, F. Javier
Palabras claveActivated receptor-gamma
Cyclopentenone prostaglandins
Cyclooxygenase-2 expression
Dependent repression
Potential inducers
Signaling pathway
Oxidative stress
Redox regulation
Fecha de publicación19-dic-2003
EditorAmerican Society for Biochemistry and Molecular Biology
CitaciónJ Biol Chem 278(51):51251-60 (2003)
ResumenCyclopentenone prostaglandins may interfere with cellular functions by multiple mechanisms. The cyclopentenone 15-deoxy-Delta 12,14-prostaglandin J2 (15d-PGJ2) has been reported to inhibit the activity of the transcription factor AP-1 in several experimental settings. We have explored the possibility of a direct interaction of 15d-PGJ2 with AP-1 proteins. Here we show that 15d-PGJ2 covalently modifies c-Jun and directly inhibits the DNA binding activity of AP-1. The modification of c-Jun occurs both in vitro and in intact cells as detected by labeling with biotinylated 15d-PGJ2 and mass spectrometry analysis. Attachment of the cyclopentenone prostaglandin occurs at cysteine 269, which is located in the c-Jun DNA binding domain. In addition, 15d-PGJ2 can promote the oligomerization of a fraction of c-Jun through the formation of intermolecular disulfide bonds or 15d-PGJ2-bonded dimers. Our results identify a novel site of interaction of 15d-PGJ2 with the AP-1 activation pathway that may contribute to the complex effects of cyclopentenone prostaglandins on the cellular response to pro-inflammatory agents. They also show the first evidence for the induction of protein cross-linking by 15d-PGJ2.
Descripción11 p.-7 fig.-1 tab.-1 sch.
Versión del editorhttp://dx.doi.org/10.1074/jbc.M309409200
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