通过与激活的二氧化受体结合来调节雌激素受体信号传递
Fumiaki Ohtake1, Ken-ichi Takeyama, Takahiro Matsumoto
1The Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
Nature
|May 30, 2003
概括
二氧化物,环境污染物,可以通过与雌激素受体 (ERs) 相互作用来模仿雌激素的作用. 激活的二氧化碳受体 (AhR) 与ER结合,影响基因转录并引起不良的雌激素作用.
科学领域:
- 环境毒理学环境毒理学
- 分子内分泌学分子内分泌学
- 基因调节 基因调节
背景情况:
- 像二氧化这样的环境污染物与生物系统具有复杂的相互作用.
- 素以抗雌激素作用而闻名,但也可以促进雌激素依赖的条件,这表明其具有双重作用.
- 在二氧化诱导的雌激素相关影响背后的精确分子机制在很大程度上仍未被阐明.
研究的目的:
- 调查二氧化物通过什么分子机制产生与雌激素相关的效应.
- 为了确定二氧化碳受体 (AhR) 途径是否与雌激素受体 (ER) 信号相互作用.
- 阐明AhR/Arnt异构体如何调节对雌激素敏感基因转录.
主要方法:
- 同免疫沉试验检测AhR/Arnt和ERs之间的蛋白质与蛋白质相互作用.
- 染色体免疫沉 (ChIP) 确定AhR/Arnt和ERs与向基因促进体的结合.
- 定量PCR和西式斑点检测用于评估基因表达和蛋白质水平.
- 在体内研究使用野生类型和淘汰赛 (AhR-/-, ER-alpha-/-) 卵巢切除的小鼠来评估子宫组织中的雌激素反应.
主要成果:
- 激活的AhR/Arnt异构体直接与ER-alpha和ER-beta结合在一起.
- 这种相互作用促进了未结合的ER和协同激活器p300的招募到对雌激素敏感基因促进体.
- 激活的AhR/Arnt复合物导致转录的激活,并表现出雌激素效应,同时减弱了联结ER的功能.
- 在野生型小鼠中观察到AhR激动剂的雌激素作用,但在AhR-/-或ER-alpha-/-小鼠中被废除.
结论:
- 激活的AhR/Arnt作为一个共同调节器,直接调节ER介导的雌激素信号传递.
- 这种新的机制解释了二氧化类环境污染物的有害雌激素相关作用.
- 研究结果显示,通过与雌激素受体通路的直接相互作用,二氧化碳暴露与内分泌干扰之间存在关键联系.
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