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Molecular and Cellular Biology, November 2006, p. 7966-7976, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.00713-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Turning Off Estrogen Receptor ß-Mediated Transcription Requires Estrogen-Dependent Receptor Proteolysis{triangledown}

Yukiyo Tateishi,1,{dagger} Raku Sonoo,2,{dagger} Yu-ichi Sekiya,1 Nanae Sunahara,1 Miwako Kawano,1 Mitsutoshi Wayama,1 Ryuichi Hirota,2 Yoh-ichi Kawabe,1 Akiko Murayama,1 Shigeaki Kato,3 Keiji Kimura,1 and Junn Yanagisawa1,2*

Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8572, Japan,1 Ankhs Incorporated, Tsukuba Industrial Liaison and Cooperative Research Center, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8577, Japan,2 Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan3

Received 25 April 2006/ Returned for modification 12 June 2006/ Accepted 17 August 2006

Recent studies have shed light on the ligand-dependent transactivation mechanisms of nuclear receptors (NRs). When the ligand dose is reduced, the transcriptional activity of NRs should be downregulated. Here we show that a ubiquitin-proteasome pathway plays a key role in turning off transcription mediated by estrogen receptor ß (ERß). ERß shows estrogen-dependent proteolysis, and its degradation is regulated by two regions in the receptor. The N-terminal 37-amino acid-region is necessary for the recruitment of the ubiquitin ligase, i.e., the carboxyl terminus of HSC70-interacting protein (CHIP), to degrade ERß. In contrast, the C-terminal F domain protects ligand-unbound ERß from proteolysis to abrogate proteasome association. Suppression of CHIP by interfering RNA inhibited this switching off of receptor-mediated transcription when the ligand dose was reduced. Our results suggest that after ligand withdrawal, the active form of the NR is selectively eliminated via ligand-dependent proteolysis to downregulate receptor-mediated transcription.

* Corresponding author. Mailing address: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8572, Japan. Phone: 81-29-853-6632. Fax: 81-29-853-4605. E-mail: junny{at}agbi.tsukuba.ac.jp.

{triangledown} Published ahead of print on 28 August 2006.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, November 2006, p. 7966-7976, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.00713-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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