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J. Biol. Chem., Vol. 278, Issue 36, 34458-34466, September 5, 2003

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The AF-1 and AF-2 Domains of RAR2 and RXR Cooperate for Triggering the Transactivation and the Degradation of RAR2/RXR Heterodimers^*

Maurizio Gianní , Anne Tarrade , Elisa Agnese Nigro ¶, Enrico Garattini ¶ and Cécile Rochette-Egly ||

From the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) CNRS INSERM ULP, UMR 7104, BP 10142, 67404 Illkirch Cedex, France and ^¶Laboratorio di Biologia Molecolare, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milano, Italy

In eukaryotic cells, liganded RAR2/RXR heterodimers activate the transcription of retinoic acid (RA) target genes and then are degraded through the ubiquitin-proteasome pathway. In this study, we dissected the role of the RAR2 and RXR partners as well as of their respective AF-1 and AF-2 domains in the processes of transactivation and degradation. RAR2 is the "engine" initiating transcription and its own degradation subsequent to ligand binding. Integrity of its AF-2 domain and phosphorylation of its AF-1 domain are required for both the degradation and the transactivation of the receptor. Deletion of the whole AF-1 domain does not impair these processes but shifts the receptor toward other proteolytic pathways through RXR. In contrast, RXR plays only a modulatory role, cooperating with RAR2 through its AF-2 domain and its phosphorylated AF-1 domain in both the transcription activity and the degradation of the RAR2/RXR heterodimers. Our results underline that the AF-1 and AF-2 domains of each heterodimer partner cooperate with one other and that this cooperation is relevant for both the transcription and degradation processes.

Received for publication, May 12, 2003 , and in revised form, June 23, 2003.

^* This work was supported by funds from CNRS, INSERM, the Collège de France, the Hôpital Universitaire de Strasbourg, the Association pour la Recherche sur le Cancer, and Bristol-Myers Squibb. This work was also supported by the "Associazione Italiana per la Ricerca contro il Cancro," the "Progetto Finalizzato Oncologia," Consiglio Nazionale delle Ricerche-Ministero dell'Università e della Ricerca Scientifica e Technologica, and the "Fondo d'Investimento per la Ricerca Biotecnologica." 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.

Supported by short term fellowships from Human Frontier Science Program, the Association pour la Recherche sur le Cancer, and the Fondazione Italiana per la Ricerca sul Cancro. Present adress: Laboratorio di Biologia Molecolare, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milano, Italy.

Supported by the "Ligue Nationale contre le Cancer." Present address: Neurogénétique Moléculaire, E.O223, Génopole, 2 rue Gaston Crémieux, 91057 Evry Cedex, France.

^|| To whom correspondence should be addressed: IGBMC, BP 10142, 67 404 Illkirch Cedex, CU de Strasbourg, France. Tel.: 33-3-88-65-34-59; Fax: 33-3-88-65-32-01; E-mail: cegly{at}igbmc.u-strasbg.fr.

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