Article
- The EMBO Journal (2004) 23, 4813 - 4823
- doi:10.1038/sj.emboj.7600472
Published online: 11 November 2004
Subject Categories:
Ligand-dependent switching of ubiquitin–proteasome pathways for estrogen receptor
Yukiyo Tateishi1,a, Yoh-ichi Kawabe1,a, Tomoki Chiba2, Shigeo Murata2, Ken Ichikawa1, Akiko Murayama1, Keiji Tanaka2, Tadashi Baba1, Shigeaki Kato3,4 and Junn Yanagisawa1,5
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan
- The Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo, Japan
- Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan
- SORST, Japan Science and Technology, Kawaguchi, Saitama, Japan
- Ankhs Inc., Tsukuba-city, Ibaraki, Japan
Correspondence to:
Junn Yanagisawa, Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tenno-dai, Tsukuba Science City, Ibaraki 305-8572, Japan. Tel.: +81 29 853 6632; Fax: +81 29 853 4605; E-mail: junny@agbi.tsukuba.ac.jp
aThese authors contributed equally to this work
Received 21 June 2004; Accepted 12 October 2004
Abstract
Recent evidence indicates that the transactivation of estrogen receptor 
(ER) requires estrogen-dependent receptor ubiquitination and degradation. Here we show that estrogen-unbound (unliganded) ER is also ubiquitinated and degraded through a ubiquitin–proteasome pathway. To investigate this ubiquitin–proteasome pathway, we purified the ubiquitin ligase complex for unliganded ER and identified a protein complex containing the carboxyl terminus of Hsc70-interacting protein (CHIP). CHIP preferentially bound to misfolded ER and ubiquitinated it to induce degradation. Ligand binding to the receptor induced the dissociation of CHIP from ER. In CHIP-/- cells, the degradation of unliganded ER was abrogated; however, estrogen-induced degradation was observed to the same extent as in CHIP+/+ cells. Our findings suggest that ER is regulated by two independent ubiquitin–proteasome pathways, which are switched by ligand binding to ER. One pathway is necessary for the transactivation of the receptor and the other is involved in the quality control of the receptor.
Keywords:
- estrogen receptor,
- nuclear receptors,
- transcription,
- ubiquitination
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