FUNCTIONAL INHIBITION OF RETINOIC ACID RESPONSE BY DOMINANT NEGATIVE RETINOIC ACID RECEPTOR MUTANTS
FUNCTIONAL INHIBITION OF RETINOIC ACID RESPONSE BY DOMINANT NEGATIVE RETINOIC ACID RECEPTOR MUTANTS
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DOI：
10.1073/pnas.90.7.2989
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发表时间：
1993-04-01
影响因子：
11.1
通讯作者：
EVANS, RM
中科院分区：
文献类型：
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作者：
DAMM, K;HEYMAN, RA;EVANS, RM
类维生素A对脊椎动物生物体的发育、生长和体内平衡的不同作用部分由维甲酸受体（RAR）的三种不同亚型介导。这些蛋白质在结构和功能上与甲状腺激素受体和癌基因产物v-ErbA密切相关，调节靶组织中的基因表达模式。研究视黄酸在细胞中的独特作用的一种方法是通过显性负性受体衍生物的表达来破坏内源性受体的这种活性。我们在这里证明，RAR α，RAR β和RAR γ可以转化为有效的负转录调节因子，阻断野生型RAR功能。此外，这些突变的RAR，而不是野生型受体，主动抑制靶启动子的基础转录水平。当在转基因小鼠中表达时，这些抑制性受体突变体中最有效的突变体显然能够通过诱导转基因后代的腭裂来干扰发育过程。
The diverse effects of retinoids on the development, growth, and homeostasis of vertebrate organisms are mediated in part by three distinct isoforms of retinoic acid receptors (RARs). These proteins, which are structurally and functionally closely related to thyroid hormone receptors and the oncogene product v-ErbA, regulate patterns of gene expression in target tissues. One approach to study the distinct effects of retinoic acid in cells is to subvert this activity of endogenous receptors by expression of dominant negative receptor derivatives. We demonstrate here that RARalpha, RARbeta, and RARgamma can be converted into potent negative transcriptional regulators that block wild-type RAR function. Furthermore, these mutant RARs, but not the wild-type receptors, actively repress the basal transcription level of target promoters. When expressed in transgenic mice, the most potent of these inhibitory receptor mutants is apparently able to disturb developmental processes by inducing a cleft palate in transgenic offspring.