Ligand-induced estrogen receptor alpha degradation by the proteasome: new actors?

In this perspective we consider new aspects of ligand-induced estrogen receptor alpha (ERalpha) degradation. What are the possible roles of CSN5/Jab1 and the CSN complex in this process? We compare hormone (estrogen) or pure antagonist (fulvestrant) induced degradation of ERalpha and review the effects of kinase-inhibitors and CRM1-dependent nuclear export on ERalpha degradation and transcription activation. A model for ERalpha action integrating these new actors is proposed and the relation between hormone-induced ERalpha degradation and transcription-activation is discussed.

CSN5/Jab1 is involved in ligand-dependent degradation of estrogen receptor {alpha} by the proteasome.

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