Nucleic Acids Research Advance Access originally published online on February 20, 2007
Nucleic Acids Research 2007 35(5):1673-1686; doi:10.1093/nar/gkl1112
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Nucleic Acids Research, 2007, Vol. 35, No. 5 1673-1686
Published by Oxford University Press 2007.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Ubiquitin-interaction motifs of RAP80 are critical in its regulation of estrogen receptor 
1Cell Biology Section, Division of Intramural Research, National Institute of Enironmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA, 2Phenex Pharmaceuticals AG, D-67056 Ludwigshafen, Germany and 3RZPD German Resource Center for Genome Research, D-69120 Heidelberg, Germany
*To whom correspondence should be addressed. Tel: 919-541-2768; Fax: 919-541-4133; E-mail: jetten{at}niehs.nih.gov
Received June 8, 2006. Revised November 10, 2006. Accepted December 6, 2006.
In this study, we demonstrate that receptor-associated protein 80 (RAP80) interacts with estrogen receptor alpha (ER
) in an agonist-dependent manner. The interaction is specific for ER as ERß and several other nuclear receptors tested did not interact with RAP80. Interaction between RAP80 and ER was supported by mammalian two-hybrid, GST pull-down, and co-immunoprecipitation analyses. The hinge/ligand-binding domain of ER is sufficient for interaction with RAP80. RAP80 overexpression reduces ER polyubiquitination, increases the level of ER protein, and enhances ER-mediated transactivation. Knockdown of endogenous RAP80 expression by small-interfering RNA (siRNA) reduced ER protein level and the E2-dependent induction of pS2. In this study, we also demonstrate that RAP80 contains two functional ubiquitin-interaction motifs (UIMs) that are able to bind ubiquitin and to direct monoubiquitination of RAP80. Deletion of these UIMs does not affect the ability of RAP80 to interact with ER, but eliminates the effects of RAP80 on ER polyubiquitination, the level of ER protein, and ER-mediated transcription. These data indicate that the UIMs in RAP80 are critical for the function of RAP80. Our study identifies ER as a new RAP80-interacting protein and suggests that RAP80 may be an important modulator of ER activity.
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