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Molecular and Cellular Biology, June 2005, p. 4349-4358, Vol. 25, No. 11
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.11.4349-4358.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

CSN5/Jab1 Is Involved in Ligand-Dependent Degradation of Estrogen Receptor {alpha} by the Proteasome

Mathilde Calligé, Isabelle Kieffer,{dagger} and Hélène Richard-Foy*

Laboratoire de Biologie Moléculaire Eucaryote, UMR 5099, Centre National de la Recherche Scientifique, Institut d'Exploration Fonctionnelle des Génomes (IFR 109), 118, route de Narbonne 31062 Toulouse, France

Received 6 October 2004/ Returned for modification 10 December 2004/ Accepted 1 March 2005

Here, we show that estrogen receptor {alpha} (ER{alpha}) coimmunoprecipitates with CSN5/Jab1, a subunit of the COP9 signalosome (CSN), and that overexpression of CSN5/Jab1 causes an increase in ligand-induced ER{alpha} degradation. Inhibition of either the kinase activity associated with the CSN complex by curcumin or of nuclear export by leptomycin B (LMB) impaired estradiol-induced ER{alpha} degradation by the proteasome. Degradation of ER{alpha} induced by the pure antagonist ICI 182,780 (ICI) was blocked by curcumin but not by LMB, indicating that in the presence of ICI, ER{alpha} is degraded by a nuclear fraction of the proteasome. In addition, we observed that curcumin inhibited estradiol-induced phosphorylation of ER{alpha}. The use of three inhibitors of ER{alpha} degradation that target different steps of the estrogen response pathway (inhibition of the CSN-associated kinase, nuclear export, and proteasome) suggests that a phosphorylation event inhibited by curcumin is necessary for ER{alpha} binding to its cognate DNA target. Our results demonstrate that transcription per se is not required for ER{alpha} degradation and that assembly of the transcription-initiation complex is sufficient to target ER{alpha} for degradation by the proteasome.

* Corresponding author. Mailing address: LBME, UMR 5099, CNRS, IEFG (IFR 109)/IBCG, 118 route de Narbonne, 31062 Toulouse, France. Phone: 33 5 61 33 59 40. Fax: 33 5 61 33 58 86. E-mail: hrfoy{at}ibcg.biotoul.fr.

{dagger} Present address: Laboratoire de Biologie Cellulaire et Moléculaire et du Contrôle de la Prolifération, UMR 5088, Centre National de la Recherche Scientifique, Institut d'Exploration Fonctionnelle des Génomes (IFR 109), 31062 Toulouse, France.

Molecular and Cellular Biology, June 2005, p. 4349-4358, Vol. 25, No. 11
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.11.4349-4358.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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