Functional differences between the amino-terminal domains of estrogen receptors α and β
Functional differences between the amino-terminal domains of estrogen receptors α and β
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DOI：
10.1124/mol.58.3.584
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发表时间：
2000-09-01
影响因子：
3.6
通讯作者：
Gustafsson, JÅ
中科院分区：
文献类型：
--
作者：
Delaunay, F;Pettersson, K;Gustafsson, JÅ
人雌激素受体α（ER α）和β（ER β）是配体诱导的转录因子，它们在其中心DNA结合域和羧基末端配体结合域中高度同源。相比之下，ER α和ER β在氨基末端结构域中的保守性非常小。使用不同的人类细胞系，我们表明，野生型ER β转录活性低于或类似于ER α，这取决于细胞类型。两种ER亚型中氨基末端结构域的缺失导致ER β的转录活性与ER α相比没有或降低较低，表明ER β氨基末端结构域包含较弱的转录激活功能-1。使用ER α和ER β缺失突变体，我们表明ER β的氨基末端转录活性映射到氨基酸1-31。有趣的是，该结构域包含6个氨基酸基序（人ER β中的氨基酸5-10），其是ER α激活功能-1区（人ER α中的氨基酸49-54）的一部分，并且在所有哺乳动物ER α氨基末端结构域中高度保守。尽管两种ER亚型之间存在这种相似性，但与ER α相比，在酵母和哺乳动物细胞中未观察到ER β-氨基末端结构域的自主和配体非依赖性活性。本研究为ER α和ER β之间转录活性的差异提供了分子基础，并确定ER β含有结构和功能受限的氨基末端转录活性。
Human estrogen receptors alpha (ER alpha) and beta (ER beta) are ligand-inducible transcription factors that are highly homologous in their central DNA-binding and carboxyl-terminal ligand-binding domains. In contrast, there is very little conservation between ER alpha and ER beta in the amino-terminal domain. Using different human cell lines, we show that wild-type ER beta transcriptional activity is lower or similar to that of ER alpha, depending on the cell type. Deletion of the amino-terminal domain in both ER subtypes resulted in no or a lower decrease of transcriptional activity of ER beta compared with ER alpha, suggesting that the ER beta amino-terminal domain contains a weaker transcriptional activation function-1. Using ER alpha and ER beta deletion mutants, we showed that the amino-terminal transcriptional activity of ER beta maps to amino acids 1-31. Interestingly, this domain contains a six amino-acid motif (amino acids 5-10 in human ER beta) that is part of the ER alpha-activation function-1 region (amino acids 49-54 in human ER alpha) and highly conserved among all mammalian ER alpha amino-terminal domains. Despite this similarity between the two ER subtypes, no autonomous and ligand-independent activity of the ER beta-amino-terminal domain was observed in yeast and mammalian cells in contrast to ER alpha. This study provides a molecular basis for the difference in transcriptional activity between ER alpha and ER beta and establishes that ER beta contains a structurally and functionally restricted amino-terminal transcriptional activity.