A COMPOSITE HORMONE RESPONSE ELEMENT MEDIATES THE TRANSACTIVATION OF THE RAT OXYTOCIN GENE BY DIFFERENT CLASSES OF NUCLEAR HORMONE RECEPTORS
A COMPOSITE HORMONE RESPONSE ELEMENT MEDIATES THE TRANSACTIVATION OF THE RAT OXYTOCIN GENE BY DIFFERENT CLASSES OF NUCLEAR HORMONE RECEPTORS
复制标题
DOI：
10.1210/me.7.1.47
复制
发表时间：
1993-01-01
影响因子：
--
通讯作者：
BURBACH, JPH
中科院分区：
文献类型：
--
作者：
ADAN, RAH;COX, JJ;BURBACH, JPH
类固醇/甲状腺激素受体超家族的转录因子是大脑发育和调节的介质。先前的研究表明，下丘脑催产素（OF）基因是这些受体的潜在靶点，因为其启动子受雌激素和甲状腺激素的刺激。这里显示，大鼠OF启动子被视黄酸通过5 '-侧翼区中的两个不同区域刺激（至少20倍）。主要的视黄酸反应元件位于核苷酸-172和-148之间，次要的位于核苷酸-112和-77之间，这是由5 '-缺失突变体的反式激活和视黄酸受体与启动子元件的结合所推断的。由于-172/-148元素也赋予雌激素和甲状腺激素反应性，因此它可以被认为是复合激素反应元素。该元件包含具有间隔零（DR-0）的半位点AGGTCA的直接重复的天然变体以及回文。通过定点诱变对该元件的核心序列进行分析表明，该元件的三个TGACC基序中的每一个都对多激素敏感性有贡献，但每个基序的贡献对于各个受体是不同的。在新生大鼠中，维生素A缺乏和维甲酸补充没有引起下丘脑OF mRNA水平和垂体和血浆中OF肽水平的变化。凝胶阻滞蛋白-DNA复合物之间的复合激素反应元件和提取物的下丘脑视上和室旁核。复合激素反应元件具有独特的构型，并整合类固醇/甲状腺激素受体超家族的多个成员的反应。
Transcription factors of the steroid/thyroid hormone receptor superfamily are mediators of development and regulation of the brain. Previous studies have shown that the hypothalamic oxytocin (OF) gene is a potential target of these receptors, since its promoter is stimulated by estrogens and thyroid hormone. Here it is shown that the rat OF promoter is stimulated (at least 20-fold) by retinoic acid through two distinct regions in the 5'-flanking region. The major retinoic acid response element was located between nucleotides -172 and -148 and a minor one between nucleotides -112 and -77, as concluded from the transactivation of 5'-deletion mutants and binding to promoter elements by the retinoic acid receptor. Since the -172/-148 element also conferred estrogen and thyroid hormone responsiveness, it can be considered a composite hormone response element. This element contains a natural variant of the direct repeat of the half-site AGGTCA with spacing zero (DR-0) as well as a palindrome. Analysis of the core sequences of this element by site-directed mutagenesis showed that each of the three TGACC motifs integral to this element contributes to the multihormone sensitivity, but the contribution of each motif is different for the individual receptors. In neonatal rats, vitamin A deficiency and retinoic acid supplementation did not cause changes in hypothalamic OF mRNA levels and OF peptide levels in the pituitary gland and plasma. Gel-retarded protein-DNA complexes were formed between the composite hormone response element and extracts of the hypothalamic supraoptic and paraventricular nuclei. The composite hormone response element has a unique configuration and integrates responses of multiple members of the steroid/thyroid hormone receptor superfamily.