Identification of RVR, a novel orphan nuclear receptor that acts as a negative transcriptional regulator.

Identification of RVR, a novel orphan nuclear receptor that acts as a negative transcriptional regulator.
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鉴定出 RVR,一种充当负转录调节因子的新型孤儿核受体。

DOI:
10.1210/mend.8.9.7838156
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发表时间:
1994
影响因子:
--
通讯作者:
V. Giguère
V. Giguère
中科院分区:
医学2区
文献类型:
--
作者:
R. Retnakaran;G. Flock;V. Giguère

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核受体类固醇/甲状腺/类视黄醇超家族的一个新成员已经被分离出来,作为筛选的一部分,以确定与最近表征的孤儿受体ROR α相关的基因。该孤儿受体从小鼠脑cDNA文库中克隆而来,与大鼠Rev-ErbA α基因产物密切相关(分别在DNA和配体结合域具有97%和68%的同源性),称为RVR。Northern blot分析显示,两种RVR mRNA在小鼠胚胎发生过程中表达,并在成年组织中广泛表达。体外翻译RVR蛋白的研究表明,它与DNA序列ATAACTAGGTCA结合,ATAACTAGGTCA是一个激素反应元件,由一个富含6碱基对at的序列组成,位于单个核受体识别半位点核心基序PuGGTCA之前。我们发现RVR识别这种激素反应元件的特异性与孤儿受体ROR α 2相似。然而,共转染研究表明,当RVR激素反应元件与报告基因连接时,RVR不会激活转录,而是作为ROR α功能的有效竞争性抑制因子。这些结果表明,存在一种基于孤儿核受体的信号通路,其内在能力通过转录激活因子和抑制因子之间对同一识别位点的竞争来调节特定基因网络的表达。
A novel member of the steroid/thyroid/retinoid superfamily of nuclear receptors has been isolated as part of a screen to identify genes related to the recently characterized orphan receptor ROR alpha. This new orphan receptor, cloned from a mouse brain cDNA library, is closely related to the rat Rev-ErbA alpha gene product (97% and 68% identity in the DNA- and ligand-binding domains, respectively) and referred to as RVR. Northern blot analysis reveals that two RVR mRNA species are expressed during mouse embryogenesis and widely expressed in adult tissues. Studies with in vitro translated RVR protein show that it binds the DNA sequence ATAACTAGGTCA, a hormone response element composed of a 6-base pair AT-rich sequence preceding a single nuclear receptor recognition half-site core motif PuGGTCA. We show that RVR recognizes this hormone response element with a specificity similar to that of the orphan receptor ROR alpha 2. However, cotransfection studies indicate that RVR does not activate transcription when this hormone response element is linked to a reporter gene but rather acts as a potent competitive repressor of ROR alpha function. These results indicate the existence of an orphan nuclear receptor-based signaling pathway with the intrinsic ability to regulate the expression of specific gene networks through competition between transcriptional activators and repressors for the same recognition site.
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