Analysis of estrogen receptor transcriptional enhancement by a nuclear hormone receptor coactivator
Analysis of estrogen receptor transcriptional enhancement by a nuclear hormone receptor coactivator
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DOI：
10.1073/pnas.93.19.10069
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发表时间：
1996-09-17
影响因子：
11.1
通讯作者：
Katzenellenbogen, BS
中科院分区：
文献类型：
--
作者：
McInerney, EM;Tsai, MJ;Katzenellenbogen, BS
雌激素受体（ER）是核激素受体大超家族的成员，是调节雌激素应答基因表达的配体诱导型转录因子。与该超家族的其他成员一样，ER含有两个转录激活功能（AF）-一个位于氨基末端区域（AF-1），第二个位于羧基末端区域（AF-2），在大多数细胞环境中，AF-1和AF-2的协同活性是完全雌二醇（E（2））刺激活性所必需的。我们以前已经证明，雌激素受体的两个含AF区域之间的配体依赖性相互作用是由E（2）和抗雌激素的反式羟基他莫昔芬（TOT）促进的。然而，这种相互作用只有在E（2）存在的情况下才能转录。为了探索类固醇受体辅激活因子在AF-1和AF-2之间的转录协同作用中的可能作用，我们在哺乳动物细胞中表达了ER的氨基末端（含AF-1）和羧基末端（含AF-2）区域作为单独的多肽，沿着类固醇受体辅激活因子-1蛋白（SRC-1）。我们证明SRC-1，这已被证明显着增加ER转录活性，增强相互作用，由E（2）或TOT介导的，AF-1和AF-2的ER区域之间。然而，这种增强的相互作用仅导致与E（2）而不是与TOT的转录有效性增加，这与SRC-1对全长受体的作用一致。我们的研究结果表明，配体结合后，SRC-1可以作为一个衔接蛋白，促进氨基和羧基末端受体功能的整合，允许完全受体激活，潜在的，SRC-1可能能够增强相关的核受体超家族成员的转录活性，通过促进这些受体中的两个含AF区域的生产性关联。
The estrogen receptor (ER), a member of a large superfamily of nuclear hormone receptors, is a ligand-inducible transcription factor that regulates the expression of estrogen-responsive genes, The ER, in common with other members of this superfamily, contains two transcription activation functions (AFs)-one located in the amino-terminal region (AF-1) and the second located in the carboxyl-terminal region (AF-2), In most cell contexts, the synergistic activity of AF-1 and AF-2 is required for full estradiol (E(2))-stimulated activity. We have previously shown that a ligand-dependent interaction between the two AF-containing regions of ER was promoted by E(2) and the antiestrogen trans-hydroxytamoxifen (TOT). This interaction, however, was transcriptionally productive only in the presence of E(2). To explore a possible role of steroid receptor coactivators in transcriptional synergism between AF-1 and AF-2, we expressed the amino terminal (AF-1-containing) and carboxyl-terminal (AF-2-containing) regions of ER as separate polypeptides in mammalian cells, along with the steroid receptor coactivator-1 protein (SRC-1). We demonstrate that SRC-1, which has been shown to significantly increase ER transcriptional activity, enhanced the interaction, mediated by either E(2) or TOT, between the AF-1-containing and AF-2-containing regions of the ER. However, this enhanced interaction resulted in increased transcriptional effectiveness only with E(2) and not with TOT, consistent with the effects of SRC-1 on the full-length receptor. Our results suggest that after ligand binding, SRC-1 may act, in part, as an adapter protein that promotes the integration of amino- and carboxyl-terminal receptor functions, allowing for full receptor activation, Potentially, SRC-1 may be capable of enhancing the transcriptional activity of related nuclear receptor superfamily members by facilitating the productive association of the two AF-containing regions in these receptors.