Peroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressors
Peroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressors
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DOI：
10.1128/mcb.17.4.2166
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发表时间：
1997-04-01
影响因子：
5.3
通讯作者：
Glass, CK
中科院分区：
文献类型：
--
作者：
DiRenzo, J;Soderstrom, M;Glass, CK
视黄酸X受体（retinoidXreceptor，RXR）是核受体异源二聚体中的一员，具有两种潜在的功能：与激素反应元件的协同结合和RXR配体对靶基因的协同调节。本文描述了RXR与两种异源二聚体受体--视黄酸受体（retinoicacidreceptor，RARs）和过氧化物酶体增殖物激活受体（peroxisomeproliferatoractivatedreceptor，PPARs）之间的变构相互作用; RAR和PPAR分别阻止和允许RXR特异性配体的激活。通过与RXR在由间隔Ibp的直接重复半位点组成的应答元件（DRL元件）上竞争二聚化，RAR和PPAR的相对丰度决定RXR信号传导途径是否将是功能性的。与阻止RXR配体结合并募集核受体辅抑制子N-CoR的RAR相反，PPAR允许SRC-1结合以响应RXR和PPAR配体，SRC-I的过表达显着增强配体依赖性转录通过PPAR γ，表明SRC-I在体内充当共激活因子，值得注意的是，RAR阻断配体与RXR结合和与辅阻遏物相互作用的能力需要CoR盒，一种位于RAR配体结合结构域N-末端区域的结构基序，CoR盒中的突变将RAR从DR 1元件上的RXR信号传导的非允许性伴侣转化为允许性伴侣。我们认为，差异招聘的辅激活子和辅阻遏物的RAR-RXR和PPAR-RXR异二聚体的转录开关，可能是重要的控制复杂的程序的基因表达，如脂肪细胞分化的基础。
As the obligate member of most nuclear receptor heterodimers, retinoid X receptors (RXRs) can potentially perform two functions: cooperative binding to hormone response elements and coordinate regulation of target genes by RXR ligands, In this paper we describe allosteric interactions between RXR and two heterodimeric partners, retinoic acid receptors (RARs) and peroxisome proliferator-activated receptors (PPARs); RARs and PPARs prevent and permit activation by RXR-specific ligands, respectively, By competing for dimerization with RXR on response elements consisting of direct-repeat half-sites spaced by 1 bp (DRL elements), the relative abundance of RAR and PPAR determines whether the RXR signaling pathway will be functional. In contrast to RAR, which prevents the binding of RXR ligands and recruits the nuclear receptor corepressor N-CoR, PPAR permits the binding of SRC-1 in response to both RXR and PPAR ligands, Overexpression of SRC-I markedly potentiates ligand-dependent transcription by PPAR gamma, suggesting that SRC-I serves as a coactivator in vivo, Remarkably, the ability of RAR to both block the binding of ligands to RXR and interact with corepressors requires the CoR box, a structural motif residing in the N-terminal region of the RAR ligand binding domain, Mutations in the CoR box convert RAR from a nonpermissive to a permissive partner of RXR signaling on DR1 elements. We suggest that the differential recruitment of coactivators and corepressors by RAR-RXR and PPAR-RXR heterodimers provides the basis for a transcriptional switch that may be important in controlling complex programs of gene expression, such as adipocyte differentiation.