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J. Biol. Chem., Vol. 278, Issue 34, 32195-32203, August 22, 2003

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Subcellular Localization and Mechanisms of Nucleocytoplasmic Trafficking of Steroid Receptor Coactivator-1^*

Larbi Amazit , Youssef Alj, Rakesh Kumar Tyagi  ¶, Anne Chauchereau ||, Hugues Loosfelt, Christophe Pichon, Jacques Pantel **, Emmanuelle Foulon-Guinchard , Philippe Leclerc , Edwin Milgrom and Anne Guiochon-Mantel ¶¶

From the INSERM U135, Hormones, Gènes et Reproduction, IFR Bicêtre, Laboratoire d'Hormonologie et Biologie Moléculaire, AP-HP, Hôpital Bicêtre, 78 rue du Général Leclerc, 94275-Le Kremlin-Bicêtre cedex, France and the Institut Fédératif de recherche Bicêtre, 80 rue du Général Leclerc, 94276 Le Kremlin-Bicêtre cedex, France

Steroid hormone receptors are ligand-stimulated transcription factors that modulate gene transcription by recruiting coregulators to gene promoters. Subcellular localization and dynamic movements of transcription factors have been shown to be one of the major means of regulating their transcriptional activity. In the present report we describe the subcellular localization and the dynamics of intracellular trafficking of steroid receptor coactivator 1 (SRC-1). After its synthesis in the cytoplasm, SRC-1 is imported into the nucleus, where it activates transcription and is subsequently exported back to the cytoplasm. In both the nucleus and cytoplasm, SRC-1 is localized in speckles. The characterization of SRC-1 nuclear localization sequence reveals that it is a classic bipartite signal localized in the N-terminal region of the protein, between amino acids 18 and 36. This sequence is highly conserved within the other members of the p160 family. Additionally, SRC-1 nuclear export is inhibited by leptomycin B. The region involved in its nuclear export is localized between amino acids 990 and 1038. It is an unusually large domain differing from the classic leucine-rich NES sequences. Thus SRC-1 nuclear export involves either an alternate type of NES or is dependent on the interaction of SRC-1 with a protein, which is exported through the crm1/exportin pathway. Overall, the intracellular trafficking of SRC-1 might be a mechanism to regulate the termination of hormone action, the interaction with other signaling pathways in the cytoplasm and its degradation.

Received for publication, January 22, 2003 , and in revised form, June 3, 2003.

^* This work was supported in part by the INSERM, the Association pour la Recherche sur le Cancer, the Ligue pour la Recherche Contre le Cancer, the Faculté de 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. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by the Ministère de la Recherche et de l'Enseignement Supérieur and the Ligue pour la recherche contre le cancer.

Present address: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.

^¶ Supported by the INSERM and the Fondation pour la Recherche Medicale.

^|| Present address: CNRS UPR9079, Oncogenèse, différenciation et transduction du signal, Institut André Lwoff, 7 rue Guy Moquet, 94800 Villejuif, France.

^** Present address: INSERM U468, Génétique Moléculaire et Physiopathologie, Institut Mondor de Médecine Moléculaire, Hôpital Henri Mondor, 94010 Créteil cedex, France.

Present address: INSERM U189, Physiopathologie Subcellulaire et Régulations Métaboliques, Faculté de Médecine Lyon-Sud, BP12, 69921 Oullins cedex, France.

^¶¶ To whom correspondence should be addressed. Tel.: 33-1-45-21-27-47; Fax: 33-1-45-21-27-51; E-mail: anne.mantel{at}bct.ap-hop-paris.fr.

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