Multiple mechanisms of chicken ovalbumin upstream promoter transcription factor-dependent repression of transactivation by the vitamin D, thyroid hormone, and retinoic acid receptors.
Multiple mechanisms of chicken ovalbumin upstream promoter transcription factor-dependent repression of transactivation by the vitamin D, thyroid hormone, and retinoic acid receptors.
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DOI：
10.1016/s0021-9258(18)53592-4
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发表时间：
1993-02
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影响因子：
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通讯作者：
A. J. Cooney;X. Leng;S. Tsai;B. W. O'malley;M. Tsai
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作者：
A. J. Cooney;X. Leng;S. Tsai;B. W. O'malley;M. Tsai
鸡卵清蛋白上游启动子转录因子（COUP-TF）是类固醇/甲状腺激素受体超家族的成员，其在细胞中的功能作用知之甚少。然而，它能够抑制维生素D3受体（VDR）、甲状腺激素受体（TR）和视黄酸受体（RAR）对靶基因的激素诱导。我们以前已经表明，COUP-TF可以结合各种各样的A/GGGTCA重复。应答元件的这种混杂识别与COUP-TF I抑制与半位点之间具有不同间距的A/GGGTCA重复序列结合的其他受体的能力相关。在这里，我们表明，阻遏这些受体的反式激活是一个普遍现象的COUP-TF亚家族，抑制也观察到COUP-TF II。这种抑制也是剂量依赖性的COUP-TF。VDR、TR和RAR活性的抑制也分别通过骨钙蛋白、肌球蛋白重链和β RAR启动子中发现的天然生理反应元件发生。在寻找COUP-TF的抑制机制时，我们发现它不涉及COUP-TF与VDR，TR和RAR之间形成可检测的功能上无活性的异二聚体。相反，我们表明，抑制的机制可能发生在三个不同的水平：（a）主动沉默的转录和双重竞争;（B）占用的DNA结合位点;（c），异源二聚体形成与类维生素A X受体，VDR，TR和RAR的辅助调节。沉默活性定位于COUP-TF的推定配体结合结构域。我们推测COUP-TF可能在调节VDR、TR和RAR的反式激活中起主要作用。
The chicken ovalbumin upstream promoter transcription factor (COUP-TF) is a member of the steroid/thyroid hormone receptor superfamily about which little is known of its functional role in the cell. However, it is able to repress hormonal induction of target genes by vitamin D3 receptor (VDR), thyroid hormone receptor (TR), and retinoic acid receptor (RAR). We have shown previously that COUP-TF can bind a wide variety of A/GGGTCA repeats. This promiscuous recognition of response elements correlates with the ability of COUP-TF I to repress other receptors that bind to A/GGGTCA repeats with different spacings between the half-sites. Here we show that repression of transactivation by these receptors is a general phenomenon for the COUP-TF subfamily, as inhibition is also observed with COUP-TF II. This repression is also dose-dependent on COUP-TF. Inhibition of VDR, TR, and RAR activities also occurs through natural physiological response elements found in the osteocalcin, myosin heavy chain, and beta RAR promoters, respectively. In search of the mechanisms of repression by COUP-TF we show that it does not involve the formation of detectable functionally inactive heterodimers between COUP-TF and VDR, TR, and RAR. Instead, we show that the mechanism of repression could occur at three different levels: (a) active silencing of transcription and dual competition for; (b) occupancy of DNA binding sites; and (c), heterodimer formation with retinoid X receptor, the coregulator of VDR, TR, and RAR. The silencing activity was localized to the putative ligand binding domain of COUP-TF. We postulate that COUP-TF may play a master role in regulating transactivation by VDR, TR, and RAR.