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首页> 外文期刊>Molecular and Cellular Biology >Retinoic acid repression of cell-specific helix-loop-helix-octamer activation of the calcitonin/calcitonin gene-related peptide enhancer.
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Retinoic acid repression of cell-specific helix-loop-helix-octamer activation of the calcitonin/calcitonin gene-related peptide enhancer.

机译：视黄酸抑制降钙素/降钙素基因相关肽增强剂的细胞特异性螺旋-环-螺旋-八聚体活化。

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We have investigated the mechanism underlying repression of calcitonin/calcitonin gene-related peptide (CT/CGRP) gene expression by retinoic acid. Retinoic acid treatment of the CA77 thyroid C-cell line decreased CT/CGRP promoter activity two- to threefold, which correlates well with the decrease in calcitonin and CGRP mRNA levels. Repression is mediated through the nuclear retinoic acid receptors (RAR) on the basis of the retinoid specificity, the sensitivity of repression (half-maximal repression at 0.2 nM), and the additional repression caused by cotransfection of an alpha-RAR expression vector. The sequences required for retinoic acid repression were localized to an 18-bp element containing cell-specific enhancer activity. The enhancer binds helix-loop-helix (HLH) and octamer transcription factors that act synergistically to activate transcription. Retinoic acid repression requires both these factors since mutations in either motif resulted in the loss of repression. Furthermore, repression was observed only in cell lines containing enhancer activity. We have used electrophoretic mobility shift assays to show that repression does not involve direct DNA binding of RAR or RAR-retinoid X receptor heterodimers. Instead, repression appears to involve interactions with the stimulatory enhancer factors. Following retinoic acid treatment, there was a specific decrease in an enhancer complex containing both HLH and octamer proteins. Formation of the HLH-octamer complex was also specifically blocked by the addition of exogenous RAR-retinoid X receptor protein. These results demonstrate that RAR can repress CT/CGRP gene transcription by interfering with combinatorial activation by cell-specific HLH and octamer proteins.
机译：我们已经研究了视黄酸抑制降钙素/降钙素基因相关肽（CT / CGRP）基因表达的潜在机制。视黄酸对CA77甲状腺C细胞系的处理将CT / CGRP启动子活性降低了2到3倍，这与降钙素和CGRP mRNA水平的降低密切相关。抑制是通过视黄醇特异性，抑制的敏感性（在0.2 nM处有一半最大抑制）和通过共转染α-RAR表达载体引起的额外抑制，通过核视黄酸受体（RAR）介导的。维甲酸抑制所需的序列被定位到一个包含细胞特异性增强子活性的18 bp的元件上。增强子结合协同作用以激活转录的螺旋-环-螺旋（HLH）和八聚体转录因子。视黄酸抑制需要这两个因素，因为任一基序的突变都会导致抑制的丧失。此外，仅在含有增强子活性的细胞系中观察到了抑制。我们已经使用电泳迁移率变动分析法来显示抑制不涉及RAR或RAR-类维生素X受体异二聚体的直接DNA结合。相反，抑制似乎涉及与刺激增强因子的相互作用。维甲酸处理后，同时含有HLH和八聚体蛋白的增强剂复合物特异性降低。 HLH-八聚体复合物的形成也通过添加外源性RAR-类视黄醇X受体蛋白而被特异性阻断。这些结果表明，RAR可以通过干扰细胞特异性HLH和八聚体蛋白的组合激活来抑制CT / CGRP基因转录。

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