Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen.
Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen.
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DOI：
10.1210/mend.11.6.0009
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发表时间：
1997-06
影响因子：
--
通讯作者：
Carolyn L. Smith;Z. Nawaz;B. O’Malley
中科院分区：
文献类型：
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作者：
Carolyn L. Smith;Z. Nawaz;B. O’Malley
混合抗雌激素，如4-羟基他莫昔芬（4 HT），作为雌激素受体（ER）的功能，在组织，细胞和启动子特异性的方式，表明细胞内因子调节其调节转录的能力的部分激动剂或拮抗剂。为了确定辅激活因子和辅阻遏因子是否具有调节4 HT的相对激动剂/拮抗剂活性的能力，在SRC-1（类固醇受体辅激活因子-1）或SMRT（视黄酸和甲状腺激素受体的沉默介体）的表达载体存在或不存在的情况下测量ER依赖性基因表达。在Hep G2细胞中，4 HT是一种激动剂，外源性SRC-1增强雌二醇（E2）和4 HT刺激的转录以剂量依赖的方式，而SMRT过表达强烈降低基础和4 HT刺激的基因表达，对E2活性没有影响。这些观察结果不是细胞或启动子特异性的，因为在HeLa细胞中在4 HT是拮抗剂的条件下获得了类似的结果。蛋白质-蛋白质相互作用试验表明，全长ER结合SMRT在体外。为了评估给定细胞内的相对辅激活因子和辅抑制因子表达是否可以调节4 HT激动剂/拮抗剂活性的平衡，SRC-1和SMRT共表达。SMRT过表达阻断SRC-1共激活4 HT刺激的基因表达，并优先抑制4 HT激动剂活性是否存在外源SRC-1。该模型系统中的累积数据表明，辅激活子和辅抑制子的相对表达可以调节ER转录活性的4 HT调节，并表明它们可能有助于混合抗雌激素激活或抑制ER介导的基因表达的组织特异性能力。
Mixed antiestrogens, such as 4-hydroxytamoxifen (4HT), act as either partial agonists or antagonists of estrogen receptor (ER) function in a tissue-, cell-, and promoter-specific manner, suggesting that intracellular factors modulate their ability to regulate transcription. To determine whether coactivators and corepressors have the capacity to modulate the relative agonist/antagonist activity of 4HT, ER-dependent gene expression was measured in the absence or presence of expression vectors for SRC-1 (steroid receptor coactivator-1) or SMRT (silencing mediator of retinoic acid and thyroid hormone receptors). In Hep G2 cells in which 4HT is an agonist, exogenous SRC-1 enhanced estradiol (E2)- and 4HT-stimulated transcription in a dose-dependent manner, while SMRT overexpression strongly reduced basal and 4HT-stimulated gene expression with no effect on E2 activity. These observations were not cell- or promoter-specific inasmuch as similar results were obtained in HeLa cells under conditions in which 4HT is an antagonist. A protein-protein interaction assay indicated that the full-length ER binds to SMRT in vitro. To assess whether relative coactivator and corepressor expression within a given cell could modulate the balance of 4HT agonist/antagonist activity, SRC-1 and SMRT were coexpressed. SMRT overexpression blocked SRC-1 coactivation of 4HT-stimulated gene expression and preferentially inhibited 4HT agonist activity whether or not exogenous SRC-1 was present. The cumulative data in this model system indicate that the relative expression of coactivators and corepressors can modulate 4HT regulation of ER transcriptional activity and suggest they could contribute to the tissue-specific ability of mixed antiestrogens to activate or inhibit ER-mediated gene expression.