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Molecular and Cellular Biology, July 2005, p. 5417-5428, Vol. 25, No. 13
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.13.5417-5428.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Differential Regulation of Estrogen-Inducible Proteolysis and Transcription by the Estrogen Receptor {alpha} N Terminus

Christopher C. Valley,1 Raphaël Métivier,2 Natalia M. Solodin,1 Amy M. Fowler,1 Mara T. Mashek,1,{dagger} Lindsay Hill,1 and Elaine T. Alarid1*

Department of Physiology, University of Wisconsin—Madison, Madison, Wisconsin 53706,1 Equipe d'Endocrinologie Moléculaire de la Reproduction (EMR), Universite de Rennes I, 35042 Rennes Cedex, France2

Received 15 November 2004/ Returned for modification 14 February 2005/ Accepted 31 March 2005

The ubiquitin-proteasome pathway has emerged as an important regulatory mechanism governing the activity of several transcription factors. While estrogen receptor {alpha} (ER{alpha}) is also subjected to rapid ubiquitin-proteasome degradation, the relationship between proteolysis and transcriptional regulation is incompletely understood. Based on studies primarily focusing on the C-terminal ligand-binding and AF-2 transactivation domains, an assembly of an active transcriptional complex has been proposed to signal ER{alpha} proteolysis that is in turn necessary for its transcriptional activity. Here, we investigated the role of other regions of ER{alpha} and identified S118 within the N-terminal AF-1 transactivation domain as an additional element for regulating estrogen-induced ubiquitination and degradation of ER{alpha}. Significantly, different S118 mutants revealed that degradation and transcriptional activity of ER{alpha} are mechanistically separable functions of ER{alpha}. We find that proteolysis of ER{alpha} correlates with the ability of ER{alpha} mutants to recruit specific ubiquitin ligases regardless of the recruitment of other transcription-related factors to endogenous model target genes. Thus, our findings indicate that the AF-1 domain performs a previously unrecognized and important role in controlling ligand-induced receptor degradation which permits the uncoupling of estrogen-regulated ER{alpha} proteolysis and transcription.

* Corresponding author. Mailing address: Department of Physiology, 1300 University Ave., 120 SMI, University of Wisconsin—Madison, Madison, WI 53706. Phone: (608) 265-9319. Fax: (608) 265-5512. E-mail: alarid{at}physiology.wisc.edu.

{dagger} Present address: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599.

Molecular and Cellular Biology, July 2005, p. 5417-5428, Vol. 25, No. 13
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.13.5417-5428.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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