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

Abstract

Here, we show that estrogen receptor α (ERα) coimmunoprecipitates with CSN5/Jab1, a subunit of the COP9 signalosome (CSN), and that overexpression of CSN5/Jab1 causes an increase in ligand-induced ERα 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 ERα degradation by the proteasome. Degradation of ERα induced by the pure antagonist ICI 182,780 (ICI) was blocked by curcumin but not by LMB, indicating that in the presence of ICI, ERα is degraded by a nuclear fraction of the proteasome. In addition, we observed that curcumin inhibited estradiol-induced phosphorylation of ERα. The use of three inhibitors of ERα 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 ERα binding to its cognate DNA target. Our results demonstrate that transcription per se is not required for ERα degradation and that assembly of the transcription-initiation complex is sufficient to target ERα for degradation by the proteasome.

ACKNOWLEDGMENTS

This work was partially supported by Ligue contre le Cancer (Tarn et Garonne), Association pour la Recherche contre le Cancer, ARECA, and Région Midi-Pyrénées. M.C. was supported by Association pour la Recherche contre le Cancer.

We thank P. Balaguer, E. Bianchi, P. Chambon, H. Loosfelt, and H. Gronemeyer for the gift of constructs and expression vectors used in this study. We are grateful to E. Käs, K. Bystricky, and M. Grigoriev for their constructive suggestions and their critical reading of the manuscript. We thank D. Villa for electronic illustrations.