Effects of selective estrogen receptor modulators (SERMs) on coactivator nuclear receptor (NR) box binding to estrogen receptors
Effects of selective estrogen receptor modulators (SERMs) on coactivator nuclear receptor (NR) box binding to estrogen receptors
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DOI：
10.1016/s1096-7192(02)00043-4
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发表时间：
2002-07-01
影响因子：
3.8
通讯作者：
Burris, TP
中科院分区：
文献类型：
--
作者：
Bramlett, KS;Burris, TP
核受体激活靶基因需要共激活剂。 p 160 蛋白是一类经过充分研究的共激活剂，它使用短核受体相互作用结构域（NR 盒）与核受体的激活配体结合结构域结合。为了研究选择性雌激素受体调节剂 (SERM) 如何影响 NR 盒招募，我们比较了在 17β-雌二醇 (E2)、4-OH 他莫昔芬 (4-OH Tam)、LY 117018（雷洛昔芬类似物）和 ICI 182780 (ICI， ER拮抗剂）。我们的共激活剂相互作用测定利用时间分辨荧光技术来评估源自三种已知 p160 共激活剂（SRC-1、-2、-3）的 10 个 NR 盒在每种配体存在下与 ER 亚型的结合。我们研究的 SERM 不会增加 NR 盒与 ERα 或 ERβ 的结合，而是有效的拮抗剂，减少雌二醇依赖性 NR 盒的结合。我们还证明了所有测试的 SERM 的反向激动作用，因为它们剂量依赖性地减少了与激素无关的 NR 盒与 ERbeta 的结合。因此，所研究的 SERM 表现为 ERα 和 ERβ NR 盒结合的拮抗剂，并且不会增加共激活剂 NR 盒与任一 ER 亚型的结合。此外，我们还检查了 E2 结合的 ERalpha 和 ERbeta 对各种天然存在的 NR 盒的偏好，包括 10 个 SRC 盒以及来自 PGC-1、TRBP、TRAP220 和 CBP 的基序。有趣的是，我们注意到一种明显的受体特异性优先相互作用模式。 (C) 2002 年爱思唯尔科学（美国）。版权所有。
Coactivators are required for activation of target genes by nuclear receptors. A well-studied class of coactivators, the p 160 proteins, use short nuclear receptor interaction domains (NR boxes) to bind to the activated ligand-binding domain of a nuclear receptor. To investigate how selective estrogen receptor modulators (SERMs) affect NR box recruitment, we compared the recruitment of p160 NR box peptides to the estrogen receptor (ER)alpha and ERbeta in the presence of 17beta-estradiol (E2), 4-OH tamoxifen (4-OH Tam), LY 117018 (a raloxifene analog), and ICI 182780 (ICI, an ER antagonist). Our coactivator interaction assay utilizes time-resolved fluorescence technology to assess the binding of the 10 NR boxes derived from the three known p160 coactivators (SRC-1, -2, -3) to the ER subtypes in the presence of each ligand. The SERMs we studied did not increase NR box binding to either ERalpha or ERbeta, but instead were potent antagonists decreasing estradiol-dependent NR box binding. We also demonstrated inverse agonism for all of the SERMs tested as they dose-dependently decreased hormone-independent NR box binding to ERbeta. Therefore, the SERMs studied behave as antagonists of ERalpha and ERbeta NR box binding and do not increase coactivator NR box binding to either ER subtype. In addition, we examined the preference of E2-bound ERalpha and ERbeta for various naturally occurring NR boxes including the 10 SRC boxes as well as the motifs from PGC-1, TRBP, TRAP220, and CBP. Interestingly, a clear preferential pattern of interaction was noted that was receptor specific. (C) 2002 Elsevier Science (USA). All rights reserved.