文章基本信息

标题：The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified
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作者：Sofia Movérare-Skrtic ; Anna E. Börjesson ; Helen H. Farman 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：3
页码：1180-1185
DOI：10.1073/pnas.1322910111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The bone-sparing effect of estrogen is primarily mediated via estrogen receptor (ER) , which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand-binding domain. It was recently demonstrated that the ER antagonist ICI 182,780 (ICI) acts as an ER agonist in uterus of mice with mutations in the ER AF-2. To evaluate the estrogen-like effects of ICI in different tissues, ovariectomized wild-type mice and mice with mutations in the ER AF-2 (ERAF-20) were treated with ICI, estradiol, or vehicle for 3 wk. Estradiol increased the trabecular and cortical bone mass as well as the uterine weight, whereas it reduced fat mass, thymus weight, and the growth plate height in wild-type but not in ERAF-20 mice. Although ICI had no effect in wild-type mice, it exerted tissue-specific effects in ERAF-20 mice. It acted as an ER agonist on trabecular bone mass and uterine weight, whereas no effect was seen on cortical bone mass, fat mass, or thymus weight. Surprisingly, a pronounced inverse agonistic activity was seen on the growth plate height, resulting in enhanced longitudinal bone growth. In conclusion, ICI uses ER AF-1 in a tissue-dependent manner in mice lacking ERAF-2, resulting in no effect, agonistic activity, or inverse agonistic activity. We propose that ER lacking AF-2 is constitutively active in the absence of ligand in the growth plate, enabling ICI to act as an inverse agonist.