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J. Biol. Chem., Vol. 278, Issue 51, 51251-51260, December 19, 2003

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Molecular Basis for the Direct Inhibition of AP-1 DNA Binding by 15-Deoxy-^12,14-prostaglandin J₂^*

Dolores Pérez-Sala, Eva Cernuda-Morollón, and F. Javier Cañada

From the Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain

Cyclopentenone prostaglandins may interfere with cellular functions by multiple mechanisms. The cyclopentenone 15-deoxy-^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.

Received for publication, August 25, 2003 , and in revised form, October 6, 2003.

^* This work was supported in part by Comunidad Autónoma de Madrid Grants 08.4/0031.1/2000 and 08.4/0025.1/2003 and Ministerio de Ciencia y Tecnología Grant SAF2000-0149, Spain. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a fellowship from Residencia de Estudiantes, Ayuntamiento de Madrid, Spain.

To whom correspondence should be addressed: Dept. de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu, 9, 28040 Madrid, Spain. Tel.: 34-91-8373112 (ext. 4212); Fax: 34-91-5360432; E-mail: dperezsala{at}cib.csic.es.

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