Genistein-mediated attenuation of tamoxifen-induced antagonism from estrogen receptor-regulated genes
Genistein-mediated attenuation of tamoxifen-induced antagonism from estrogen receptor-regulated genes
复制标题
DOI：
10.1006/bbrc.1998.9751
复制
发表时间：
1998-12-09
影响因子：
3.1
通讯作者：
Brooks, SC
中科院分区：
文献类型：
--
作者：
Schwartz, JA;Liu, GZ;Brooks, SC
在这项研究中，我们证明，生理浓度的染料木黄酮足以介导激动和逆转抑制作用的4-羟基他莫昔芬对雌激素受体（ER α）的反应报告基因。我们还表明，类固醇受体辅激活因子（SRC-1）的过度表达增强了染料木黄酮激活的ER α的反式激活，CBP（cAMP反应元件结合蛋白辅激活因子）的共表达协同增加了这一信号。然而，外源性表达的核受体辅阻遏物（NCoR），不能改变染料木素介导的反式激活。在体外结合试验中，我们发现，染料木黄酮，而不是4-羟基他莫昔芬，诱导放射性标记的ER α和GST-SRC-1融合蛋白之间的直接相互作用。更重要的是，与染料木黄酮和4-羟基他莫昔芬共孵育或在ER与4-羟基他莫昔芬预孵育后进行染料木黄酮处理也导致与SRC-1的强物理相互作用。这些研究结果表明，金雀异黄素诱导的变化，在辅调节状态的ER α可能参与转录调控，并表明他莫昔芬介导的拮抗作用在ER依赖基因是敏感的衰减低水平的金雀异黄素。(C)北京：科学出版社.
In this study we demonstrate that physiologic concentrations of genistein are sufficient to mediate agonism and to reverse the repressive effects of 4-hydroxytamoxifen on estrogen receptor (ER alpha)-responsive reporter genes. We also show that overexpression of the steroid receptor coactivator (SRC-1) potentiates transactivation by genistein-activated ER alpha and that coexpression of CBP (the cAMP response element binding protein coactivator) synergistically increases this signal. Exogenous expression of a nuclear receptor corepressor (NCoR) was, however, unable to alter genistein-mediated transactivation. In in vitro binding assays, we show that genistein, but not 4-hydroxytamoxifen, induces a direct interaction between radiolabeled ER alpha and a GST-SRC-1 fusion protein. More importantly, coincubation with genistein and 4-hydroxytamoxifen or genistein treatment following preincubation of the ER with 4-hydroxytamoxifen also resulted in a strong physical interaction with SRC-1. These findings imply that genistein-induced shifts in the coregulator status of ER alpha may be involved in transcriptional regulation and suggest that tamoxifen-mediated antagonism at ER-dependent genes is sensitive to attenuation by low levels of genistein. (C) 1998 Academic Press.