Phosphorylation of Activation Function-1 Regulates Proteasome-Dependent Nuclear Mobility and E6-Associated Protein Ubiquitin Ligase Recruitment to the Estrogen Receptor β

The ubiquitin-proteasome pathway has been recognized as an important regulator in the hormonal response by estrogen receptor (ER) α, but its impact on ERβ function is poorly characterized. In the current study, we investigated the role of the ubiquitin-proteasome pathway in regulating ERβ activity a...

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Bibliographic Details
Published in:Molecular endocrinology (Baltimore, Md.) Md.), 2008-02, Vol.22 (2), p.317-330
Main Authors: Picard, Nathalie, Charbonneau, Catherine, Sanchez, Mélanie, Licznar, Anne, Busson, Muriel, Lazennec, Gwendal, Tremblay, André
Format: Article
Language:English
Subjects:
Animals
Binding Sites - genetics
Cancer
Cell Line
Cell Nucleus - metabolism
Consensus Sequence
Estrogen Receptor alpha - genetics
Estrogen Receptor alpha - metabolism
Estrogen Receptor beta - genetics
Estrogen Receptor beta - metabolism
Fluorescence Recovery After Photobleaching
Humans
Immunoblotting
Immunoprecipitation
Leupeptins - pharmacology
Life Sciences
Mice
Models, Biological
Mutation
Phosphorylation
Proteasome Endopeptidase Complex - genetics
Proteasome Endopeptidase Complex - metabolism
Proteasome Inhibitors
Serine - genetics
Serine - metabolism
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
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Summary:The ubiquitin-proteasome pathway has been recognized as an important regulator in the hormonal response by estrogen receptor (ER) α, but its impact on ERβ function is poorly characterized. In the current study, we investigated the role of the ubiquitin-proteasome pathway in regulating ERβ activity and identified regulatory sites within the activation function (AF)-1 domain that modulate ERβ ubiquitination and nuclear dynamics in a hormone-independent manner. Although both ERα and ERβ were dependent on proteasome function for their maximal response to estrogen, they were regulated differently by proteasome inhibition in the absence of hormone, an effect shown to be dependent on their respective AF-1 domain. Given the role of AF-1 phosphorylation to regulate ER activity, we found that sequential substitutions of specific serine residues contained in MAPK consensus sites conferred transcriptional activation of ERβ in a proteasome-dependent manner through reduced ubiquitination and enhanced accumulation of mutant receptors. Specifically, serines 94 and 106 within ERβ AF-1 domain were found to modulate subnuclear mobility of the receptor to transit between inactive clusters and a more mobile state in a proteasome-dependent manner. In addition, cellular levels of ERβ were regulated through these sites by facilitating the recruitment of the ubiquitin ligase E6-associated protein in a phosphorylation-dependent manner. These findings suggest a role for ERβ AF-1 in contributing to the activation-degradation cycling of the receptor through a functional clustering of phosphorylated serine residues that cooperate in generating signals to the ubiquitin-proteasome pathway.
ISSN:0888-8809
1944-9917
DOI:10.1210/me.2007-0281