Glucocorticoid receptor ligand binding domain is sufficient for the modulation of glucocorticoid induction properties by homologous receptors, coactivator transcription intermediary factor 2, and Ubc9
Glucocorticoid receptor ligand binding domain is sufficient for the modulation of glucocorticoid induction properties by homologous receptors, coactivator transcription intermediary factor 2, and Ubc9
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DOI：
10.1210/me.2004-0134
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发表时间：
2005-02-01
影响因子：
--
通讯作者：
Simons, SS
中科院分区：
文献类型：
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作者：
Cho, SY;Kagan, BL;Simons, SS
有几个因素调节类固醇受体激动剂复合物的剂量-反应曲线的位置和拮抗剂复合物的部分激动剂活性，从而引起循环激素的差异基因激活和抗类固醇内分泌治疗期间的不平等基因抑制。我们现在问是否调节活性的三个因素（同源受体，共激活转录中介因子2，和Ubc 9）需要相同或不同的域的糖皮质激素受体（GR）。在所有情况下，我们发现，既不需要受体的氨基末端的一半，其中包含激活功能-1激活结构域，也不需要DNA结合域。这与活化功能-1在确定基因表达量和抗类固醇与大多数类固醇受体的部分激动剂活性中的主要作用形成对比。然而，Ubc 9的情况更复杂，在低GR浓度下，GR N-末端序列阻止Ubc 9的作用，但不阻止添加的GR或转录中间因子2。通过删除这些序列或用孕酮受体的类似区域替代而不是通过抑制序列的过表达来减轻抑制。这些结果加上C-末端GR序列与抑制性N-末端结构域的结合暗示了在低GR浓度下抑制Ubc 9作用的分子内机制。在高GR浓度下，从非合作性到合作性类固醇结合的转变表明，构象变化重新定位了抑制性N-末端序列，以允许Ubc 9与配体结合结构域的元素相互作用。总的来说，这些结果表明GR C-末端序列在调节GR复合物的剂量-反应曲线和部分激动剂活性中起主导作用。它们还揭示了个体调节剂之间以及相同因子调节基因表达总量的能力之间的机制差异。
Several factors modulate the position of the dose-response curve of steroid receptor-agonist complexes and the partial agonist activity of antagonist complexes, thereby causing differential gene activation by circulating hormones and unequal gene repression during endocrine therapies with antisteroids. We now ask whether the modulatory activity of three factors (homologous receptor, coactivator transcription intermediary factor 2, and Ubc9) requires the same or different domains of glucocorticoid receptors (GRs). In all cases, we find that neither the amino terminal half of the receptor, which contains the activation function-1 activation domain, nor the DNA binding domain is required. This contrasts with the major role of activation function-1 in determining the amount of gene expression and partial agonist activity of antisteroids with most steroid receptors. However, the situation is more complicated with Ubc9, where GR N-terminal sequences prevent the actions of Ubc9, but not added GR or transcription intermediary factor 2, at low GR concentrations. Inhibition is relieved by deletion of these sequences or by replacement with the comparable region of progesterone receptors but not by overexpression of the repressive sequences. These results plus the binding of C-terminal GR sequences to the suppressive N-terminal domain implicate an intramolecular mechanism for the inhibition of Ubc9 actions at low GR concentrations. A shift from noncooperative to cooperative steroid binding at high GR concentrations suggests that conformational changes reposition the inhibitory N-terminal sequence to allow Ubc9 interaction with elements of the ligand binding domain. Collectively, these results indicate a dominant role of GR C-terminal sequences in the modulation of the dose-response curve and partial agonist activity of GR complexes. They also reveal mechanistic differences both among individual modulators and between the ability of the same factors to regulate the total amount of gene expression.