THYROID-HORMONE RECEPTOR TRANSCRIPTIONAL ACTIVITY IS POTENTIALLY AUTOREGULATED BY TRUNCATED FORMS OF THE RECEPTOR
THYROID-HORMONE RECEPTOR TRANSCRIPTIONAL ACTIVITY IS POTENTIALLY AUTOREGULATED BY TRUNCATED FORMS OF THE RECEPTOR
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DOI：
10.1128/mcb.12.5.2406
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发表时间：
1992-05-01
影响因子：
5.3
通讯作者：
EISENMAN, RN
中科院分区：
文献类型：
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作者：
BIGLER, J;HOKANSON, W;EISENMAN, RN
ErbA/甲状腺激素受体是一种核受体，其可以以甲状腺激素（T3）依赖性方式影响从含有甲状腺激素应答元件（TRE）的启动子的转录。我们早先报道了甲状腺激素受体在胚胎禽类红系细胞中表达为具有共同C末端的四种蛋白质的嵌套组。全长受体能够高亲和力结合甲状腺激素和特异性结合DNA。我们现在报告说，两个最小的ErbA形式，其中包含的酶结合结构域，但缺乏N-末端DNA结合结构域，具有相同的亲和力T3的全长ErbA，但不能特异性DNA结合。在反式激活试验中，这些N-末端截短的蛋白能够特异性抑制全长ErbA的转录抑制和依赖于ErbA的转录激活。我们还发现，视黄酸依赖性的反式激活视黄酸受体被截断的ErbA蛋白抑制。此外，较小的ErbA形式在体外抑制全长ErbA与TREs的结合。从涉及较小的ErbA蛋白的结合结构域内的保守区域的位点特异性诱变的实验结果表明，较小的受体形式的抑制作用是独立的激素结合，并且该区域在介导蛋白质-激素以及蛋白质-蛋白质相互作用中是重要的。我们还发现，只有在特定的DNA结合位点的存在下，才能检测到全长ErbA同源二聚体。然而，全长和N-末端截短的非DNA结合ErbA蛋白之间没有关联可以检测到，这表明该复合物是不稳定的或不形成。我们的研究结果表明，受体功能的抑制发生通过瞬时形成的异源二聚体，缺乏DNA结合活性或竞争的因素，积极影响DNA结合的全长蛋白质。这一发现提出了甲状腺激素受体转录活性通过以显性负性方式起作用的替代受体翻译产物进行自动调节的可能性。
ErbA/thyroid hormone receptor is a nuclear receptor that can affect transcription from promoters containing a thyroid hormone response element (TRE) in a thyroid hormone (T3)-dependent manner. We reported earlier that the thyroid hormone receptor is expressed in embryonic avian erythroid cells as a nested set of four proteins with a common C terminus. The full-length receptor is capable of both high-affinity binding to thyroid hormone and specific binding to DNA. We now report that the two smallest ErbA forms, which contain the hormone-binding domain but lack the N-terminal DNA-binding domain, have the same affinity for T3 as does full-length ErbA but are incapable of specific DNA binding. In transactivation assays, these N-terminally truncated proteins are able to specifically suppress both transcriptional repression and hormone-dependent transcriptional activation by the full-length ErbA. We also find that retinoic acid-dependent transactivation by retinoic acid receptors is inhibited by the truncated ErbA proteins. Furthermore, the smaller ErbA forms inhibit binding to TREs by full-length ErbA in vitro. Results from experiments involving site-specific mutagenesis of a conserved region within the hormone-binding domain of the smaller ErbA proteins indicate that the suppressive effect of the smaller receptor forms is independent of hormone binding and that this region is important in mediating protein-hormone as well as protein-protein interactions. We have also found that full-length ErbA homodimers can be detected only in the presence of a specific DNA-binding site. However, no association between full-length and the N-terminally truncated non-DNA-binding ErbA proteins could be detected, indicating that the complex either is unstable or does not form. Our results suggest that inhibition of receptor function occurs through transient formation of heterodimers which lack DNA-binding activity or by competition for factors which positively affect DNA binding by the full-length protein. This finding raises the possibility that thyroid hormone receptor transcriptional activity is autoregulated by means of alternative receptor translation products acting in a dominant negative manner.