CSN5/Jab1 is involved in ligand-dependent degradation of estrogen receptor α by the proteasome

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.