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.
Calligé
Mathilde
M
LBME, UMR 5099, CNRS, IEFG (IFR 109)/IBCG, 118 route de Narbonne, 31062 Toulouse, France.
Kieffer
Isabelle
I
Richard-Foy
Hélène
H
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000075686:COP9 Signalosome Complex; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D051379:Mice; D041681:NIH 3T3 Cells; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011506:Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D005231:Fatty Acids, Unsaturated; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D011506:Proteins; C051838:TFF1 protein, human; D014157:Transcription Factors; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D004958:Estradiol; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; C501490:Cops5 protein, mouse; D000075686:COP9 Signalosome Complex; D046988:Proteasome Endopeptidase Complex; D003474:Curcumin; C038753:leptomycin B