Characterization of three RXR genes that mediate the action of 9-cis retinoic acid.

Howard Hughes Medical Institute, Ashburn, Virginia, United States
Genes & Development (Impact Factor: 12.64). 04/1992; 6(3):329-44. DOI: 10.1101/gad.6.3.329
Source: PubMed

ABSTRACT An understanding of the differences and similarities of the retinoid X receptor (RXR) and retinoic acid receptor (RAR) systems requires knowledge of the diversity of their family members, their patterns of expression, and their pharmacological response to ligands. In this paper we report the isolation of a family of mouse RXR genes encoding three distinct receptors (RXR alpha, beta, and gamma). They are closely related to each other in their DNA- and ligand-binding domains but are quite divergent from the RAR subfamily in both structure and ligand specificity. Recently, we demonstrated that all-trans retinoic acid (RA) serves as a "pro-hormone" to the isomer 9-cis RA, which is a high-affinity ligand for the human RXR alpha. We extend those findings to show that 9-cis RA is also "retinoid X" for mouse RXR alpha, beta, and gamma. Trans-activation analyses show that although all three RXRs respond to a variety of endogenous retinoids, 9-cis RA is their most potent ligand and is up to 40-fold more active than all-trans RA. Northern blot and in situ hybridization analyses define a broad spectrum of expression for the RXRs, which display unique patterns and only partially overlap themselves and the RARs. This study suggests that the RXR family plays critical roles in diverse aspects of development, from embryo implantation to organogenesis and central nervous system differentiation, as well as in adult physiology.


Available from: Uwe Borgmeyer, Apr 21, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Various synthetic chemicals are ligands for nuclear receptors (NRs) and can cause adverse effects in vertebrates mediated by NRs. While several model vertebrates, such as mouse, chicken, western clawed frog and zebrafish, are widely used in toxicity testing, few NRs have been well described for most of these classes. In this report, NRs in genomes of 12 vertebrates are characterized via bioinformatics approaches. Although numbers of NRs varied among species, with 40-42 genes in birds to 66-74 genes in teleost fishes, all NRs had clear homologs in human and could be categorized into seven subfamilies defined as NR0B-NR6A. Phylogenetic analysis revealed conservative evolutionary relationships for most NRs, which were consistent with traditional morphology-based systematics, except for some exceptions in Dolphin (Tursiops truncatus). Evolution of PXR and CAR exhibited unexpected multiple patterns and the existence of CAR possibly being traced back to ancient lobe-finned fishes and tetrapods (Sarcopterygii). Compared to the more conservative DBD of NRs, sequences of LBD were less conserved: Sequences of THRs, RARs and RXRs were ≥90% similar to those of the human, ERs, AR, GR, ERRs and PPARs were more variable with similarities of 60%-100% and PXR, CAR, DAX1 and SHP were least conserved among species.
    Scientific Reports 02/2015; 5:8554. DOI:10.1038/srep08554 · 5.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Glucose metabolism is balanced by glycolysis and gluconeogenesis with precise control in the liver. The expression of genes related to glucose metabolism is regulated primarily by glucose and insulin at transcriptional level. Nuclear receptors play important roles in regulating the gene expression of glucose metabolism at transcriptional level. Some of these nuclear receptors form heterodimers with RXRs to bind to their specific regulatory elements on the target promoters. To date, three isotypes of RXRs have been identified; RXRα, RXRβ and RXRγ. However, their involvement in the interactions with other nuclear receptors in the liver remains unclear. In this study, we found RXRγ is rapidly induced after feeding in the mouse liver, indicating a potential role of RXRγ in controlling glucose or lipid metabolism in the fasting-feeding cycle. In addition, RXRγ expression was upregulated by glucose in primary hepatocytes. This implies that glucose metabolism governed by RXRγ in conjunction with other nuclear receptors. The luciferase reporter assay showed that RXRγ as well as RXRα increased SREBP-1c promoter activity in hepatocytes. These results suggest that RXRγ may play an important role in tight control of glucose metabolism in the fasting-feeding cycle. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 01/2015; 458(1). DOI:10.1016/j.bbrc.2015.01.082 · 2.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In the present study, we analyzed the influence of retinoic acids on the expression of α-1 acid glycoprotein (AGP). We show that in rat primary hepatocytes, 9-cis retinoic acid and all-trans retinoic acid increase AGP gene expression at the transcriptional level. Transient transfections of rat primary hepatocytes with a reporter construct driven by the rat AGP gene promoter indicated that retinoids regulate AGP gene expression via the −763/−138 region of the AGP promoter. Furthermore, cotransfection experiments with retinoic acid receptor alpha (RARα) and retinoid X receptor alpha (RXRα) expression vectors in NIH3T3 cells demonstrated that both RXRα/RXRα homodimer and RXRα/RARα heterodimer are competent for ligand-induced transactivation of the AGP promoter. Unilateral deletion and site-directed mutagenesis identified two retinoic-acid responsive elements (RARE), RARE-I and RARE-II, which interestingly correspond to a direct repeat of two TGACCT-related hexanucleotides separated by a single bp only (DR1-type response element). Cotransfection assays showed that RXRα and RARα activate AGP gene transcription through these two elements either as a homodimer (RXRα/RXRα) or as a heterodimer (RXRα/RARα). The RXRα/RXRα homodimer acts most efficiently through the RARE-I response element to promote AGP transactivation, whereas the RXRα/RARα heterodimer mediates transactivation better via the RARE-II responsive element.
    Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 05/2004; 1678(2-3):135-144. DOI:10.1016/S0167-4781(04)00060-0 · 1.70 Impact Factor