Turning Off Estrogen Receptor β-Mediated Transcription Requires Estrogen-Dependent Receptor Proteolysis
Turning Off Estrogen Receptor β-Mediated Transcription Requires Estrogen-Dependent Receptor Proteolysis
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DOI：
10.1128/mcb.00713-06
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发表时间：
2006-08
影响因子：
5.3
通讯作者：
Yukiyo Tateishi;Raku Sonoo;Yu-ichi Sekiya;Nanae Sunahara;Miwako Kawano;Mitsutoshi Wayama;R. Hirota;Yoh‐ichi Kawabe;A. Murayama;S. Kato;K. Kimura;J. Yanagisawa
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文献类型：
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作者：
Yukiyo Tateishi;Raku Sonoo;Yu-ichi Sekiya;Nanae Sunahara;Miwako Kawano;Mitsutoshi Wayama;R. Hirota;Yoh‐ichi Kawabe;A. Murayama;S. Kato;K. Kimura;J. Yanagisawa
摘要近年来的研究揭示了核受体（NR）的配体依赖性反式激活机制。当配体剂量减少时，NR的转录活性应该下调。在这里，我们发现泛素-蛋白酶体途径在关闭雌激素受体β（ERβ）介导的转录中起着关键作用。ERβ表现出雌激素依赖性的蛋白水解，其降解受受体中的两个区域调节。N-末端37个氨基酸的区域对于泛素连接酶的募集是必需的，即，HSC 70相互作用蛋白（CHIP）的羧基端，降解ERβ。相反，C-末端F结构域保护未结合配体的ERβ免于蛋白水解以消除蛋白酶体缔合。当配体剂量减少时，通过干扰RNA抑制CHIP抑制了受体介导的转录的关闭。我们的研究结果表明，配体撤出后，NR的活性形式选择性地消除通过配体依赖性蛋白水解下调受体介导的转录。
ABSTRACT 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 β (ERβ). ERβ 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 ERβ. In contrast, the C-terminal F domain protects ligand-unbound ERβ 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.