Zhang X K, Wills K N, Graupner G, Tzukerman M, Hermann T, Pfahl M
Cancer Center, La Jolla Cancer Research Foundation, CA 92037.
New Biol. 1991 Feb;3(2):169-81.
We report here that the thyroid hormone receptors TR alpha and TR beta, and the retinoic acid receptor, RAR, can bind cooperatively to the thyroid hormone response elements (TRE) in both the presence and absence of ligand. Although the transcriptional synergism induced by such cooperative DNA binding could also be influenced by the position of the DNA-binding site on the promoter, the strength of the receptor-DNA interaction in the absence of the cognate ligand of each receptor was in general correlated with the repression activity. The strong-binding TRs, but not the weaker-binding RAR, allowed repression of a constitutive promoter. In addition, strong-binding receptors could repress transcriptional activation of weaker-binding receptors on the TRE. We also show here that the presence of thyroid hormone affects the cooperative DNA binding of TR beta to a TRE dimer by increasing the dissociation rate and decreasing the association rate of TR beta with the DNA. Hybrid receptor analysis revealed that receptor-DNA interaction and repressor activity are largely influenced by the ligand-binding domain of the receptor. We used deletion analysis to localize the sequences conferring a negative effect of thyroid hormone on TR beta binding to DNA and on receptor dimerization or oligomerization. Our data indicate that the ligand-binding domain of thyroid hormone receptors has an essential role in DNA binding and repressor functions, and that this domain exerts its effects by controlling receptor dimerization and oligomerization in the absence and presence of ligand.
我们在此报告，无论有无配体，甲状腺激素受体TRα和TRβ以及视黄酸受体RAR都能协同结合到甲状腺激素反应元件（TRE）上。尽管这种协同DNA结合诱导的转录协同作用也可能受启动子上DNA结合位点位置的影响，但在缺乏各受体同源配体的情况下，受体与DNA相互作用的强度通常与抑制活性相关。强结合的TRs能抑制组成型启动子，而弱结合的RAR则不能。此外，强结合受体可抑制TRE上弱结合受体的转录激活。我们还在此表明，甲状腺激素的存在通过增加TRβ与DNA的解离速率并降低其结合速率，影响TRβ与TRE二聚体的协同DNA结合。杂交受体分析显示，受体与DNA的相互作用及抑制活性在很大程度上受受体配体结合域的影响。我们通过缺失分析来定位赋予甲状腺激素对TRβ与DNA结合以及受体二聚化或寡聚化产生负面影响的序列。我们的数据表明，甲状腺激素受体的配体结合域在DNA结合和抑制功能中起关键作用，并且该结构域通过在有无配体的情况下控制受体二聚化和寡聚化来发挥其作用。
