PROTEIN SYNTHESIS POST-TRANSLATION MODIFICATION AND DEGRADATION
Sumoylation of the Progesterone Receptor and of the Steroid Receptor Coactivator SRC-1*

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SUMO-1 (small ubiquitin-like modifier) conjugation regulates the subcellular localization, stability, and activity of a variety of proteins. We show here that SUMO-1 overexpression markedly enhances progesterone receptor (PR)-mediated gene transcription. PR undergoes a sumoylation at lysine 388 located in its N-terminal domain. However, sumoylation of the receptor is not responsible for enhanced transcription because substitution of its target lysine did not abolish the effect of SUMO-1 and even converted the receptor into a slightly more active transactivator. Furthermore estrogen receptor α (ERα)-driven transcription is also enhanced by SUMO-1 overexpression contrasting with the absence of sumoylation of this receptor. We thus analyzed SUMO-1 conjugation to the steroid receptor coactivator SRC-1. We showed that this protein contains two major sites of conjugation at Lys-732 and Lys-774. Sumoylation was shown to increase PR-SRC-1 interaction and to prolong SRC-1 retention in the nucleus. It did not prevent SRC-1 ubiquitinylation and did not exert a clear effect on the stability of the protein. Overexpression of SUMO-1 enhanced PR-mediated gene transcription even in the presence of non-sumoylated mutants of SRC-1. This observation suggests that among the many protein partners involved in steroid hormone-mediated gene regulation several are probably targets of SUMO-1 modification.

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Published, JBC Papers in Press, January 14, 2003, DOI 10.1074/jbc.M207148200

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This work was supported by INSERM, the Association pour la Recherche sur le Cancer, the Ligue contre le Cancer, the Facultéde Médecine Paris-Sud, and the Fondation pour la Recherche Médicale.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked 舠advertisement舡 in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: CNRS UPR9079, Oncogénèse, différenciation et Transduction du signal, Institut AndréLwoff, 7 rue Guy Môquet, 94800 Villejuif, France.

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Supported by the Association pour la Recherche sur le Cancer.