HGNC Approved Gene Symbol: RXRA
Cytogenetic location: 9q34.2 Genomic coordinates (GRCh38): 9:134,326,455-134,440,585 (from NCBI)
Retinoic acid has been implicated in many aspects of vertebrate development and homeostasis. Its effects are mediated by specific nuclear receptor proteins that are members of the steroid and thyroid hormone receptor superfamily of transcriptional regulators. In addition to the high affinity retinoic acid receptors termed alpha (RARA; 180240), beta (RARB; 180220), and gamma (RARG; 180190), Mangelsdorf et al. (1990, 1991) identified a distinct nuclear receptor referred to as retinoid X receptor alpha. This receptor differs from the other 3 RARs within the ligand-binding domain and is incapable of high affinity binding of retinoic acid itself. The retinoic acid, thyroid hormone, and vitamin D receptors, as well as the retinoid X receptor, activate transcription from response elements containing 2 or more degenerate copies of the consensus motif AGGTCA. Heyman et al. (1992) presented evidence that 9-cis retinoic acid is a high affinity ligand for RXRA.
Zhou et al. (1995) used an in vitro model system of cardiac muscle cell hypertrophy to identify a retinoic acid-mediated pathway that suppresses the acquisition of specific features of the hypertrophic phenotype after exposure to the alpha-adrenergic receptor agonist phenylephrine. They found that retinoic acid at physiologic concentrations suppressed the increase in cell size and induction of a genetic marker for hypertrophy, namely the atrial natriuretic factor gene (ANF; 108780). Retinoic acid also suppressed endothelin-1 (EDN1; 131240) pathways for cardiac muscle cell hypertrophy. These and results of further studies suggested the possibility that a pathway for suppression of hypertrophy may exist in vivo, which may have potential therapeutic value.
RXRA can function as a homodimer and as an RXRA/RAR heterodimer, and these modes define 2 distinct retinoid response pathways. As a heterodimeric partner to RARs, RXRA does not bind ligand but rather serves as a cofactor. Willy et al. (1995) reported that RXRA and the nuclear receptor LXRA (602423) form a functional heterodimer in which RXRA is the active ligand-binding subunit. They stated that this interaction defines a third retinoid response system with a novel target gene specificity.
Tontonoz et al. (1994) identified a novel adipocyte-specific transcription factor, which they termed ARF6, and showed that it is a heterodimeric complex of RXRA and the peroxisome proliferator-activator receptor gamma (PPARG; 601487).
McNamara et al. (2001) reported a hormone-dependent interaction of the nuclear receptors RARA and RXRA with CLOCK (601851) and MOP4 (603347). They found that these interactions negatively regulate CLOCK-BMAL1 (602550) and MOP4-BMAL1 heterodimer-mediated transcriptional activation of clock gene expression in vascular cells. MOP4 exhibited a robust rhythm in the vasculature, and retinoic acid could phase shift PER2 (603426) mRNA rhythmicity in vivo and in serum-induced smooth muscle cells in vitro, providing a molecular mechanism for hormonal control of clock gene expression. McNamara et al. (2001) proposed that circadian or periodic availability of nuclear hormones may play a critical role in resetting a peripheral vascular clock.
Fusion of PML (102578) and TIF1A (603406) to RARA and BRAF (164757), respectively, results in the production of PML-RAR-alpha and TIF1-alpha-B-RAF (T18) oncoproteins. Zhong et al. (1999) showed that PML, TIF1-alpha, and RXR-alpha/RAR-alpha function together in a retinoic acid-dependent transcription complex. Zhong et al. (1999) found that PML acts as a ligand-dependent coactivator of RXR-alpha/RARA-alpha. T18, similar to PML-RAR-alpha, disrupts the retinoic acid-dependent activity of this complex in a dominant-negative manner, resulting in a growth advantage. PML-RAR-alpha was the first example of an oncoprotein generated by the fusion of 2 molecules participating in the same pathway, specifically the fusion of a transcription factor to one of its own cofactors. Since the PML and RAR-alpha pathways converge at the transcriptional level, there is no need for a double-dominant-negative product to explain the pathogenesis of acute promyelocytic leukemia, or APL.
Germain et al. (2002) showed that RXR can bind ligand and recruit coactivators as a heterodimer with apo-retinoic acid receptor (apo-RAR). However, in the usual cellular environment corepressors do not dissociate and they prohibit coactivator access because coregulator binding is mutually exclusive.
Using yeast 2-hybrid analysis and protein pull-down assays, Takano et al. (2004) showed that RNF8 (611685) and RXRA interacted via their N-terminal regions. Overexpression of RNF8 in COS-7 cells resulted in interaction and colocalization of RNF8 and RXRA in the nucleus. A point mutation in RNF8 that disrupted the RING finger or deletion of the N-terminal region of RNF8 prevented localization of RNF8 to the nucleus without affecting nuclear localization of RXRA. Transient overexpression of RNF8 enhanced RXRA-mediated transactivation of an RXR-responsive element (RXRE) in a dose-dependent and retinoic acid-independent manner and upregulated expression of genes downstream of RXRE. Enhancement of transactivation was not seen with RNF8 carrying the RING finger-disrupting mutation or the N-terminal deletion. Takano et al. (2004) concluded that RNF8 is a regulator of RXRA-mediated transcriptional activity.
Crystal Structure
The nuclear receptor PPARG (601487)/RXRA heterodimer regulates glucose and lipid homeostasis and is the target for the antidiabetic drugs GI262570 and the thiazolidinediones. Gampe et al. (2000) reported the crystal structures of the PPARG and RXRA ligand-binding domains complexed with the RXRA ligand 9-cis-retinoic acid, the PPARG agonist GI262570, and coactivator peptides. The structures provided a molecular understanding of the ability of RXRs to heterodimerize with many nuclear receptors and of the permissive activation of the PPARG/RXRA heterodimer by 9-cis-retinoic acid.
Chandra et al. (2008) presented structures of intact PPAR-gamma and RXR-alpha as a heterodimer bound to DNA, ligands, and coactivator peptides. PPAR-gamma and RXR-alpha form a nonsymmetric complex, allowing the ligand-binding domain of PPAR-gamma to contact multiple domains in both proteins. Three interfaces link PPAR-gamma and RXR-alpha, including some that are DNA-dependent. The PPAR-gamma ligand-binding domain cooperates with both DNA-binding domains to enhance response-element binding. The A/B segments are highly dynamic, lacking folded substructures despite their gene-activation properties.
Jones et al. (1993) mapped the RXRA gene to chromosome 9 by using PCR on a panel of somatic cell hybrids. A cosmid clone was isolated using the RXRA PCR product, and this was used to localize the gene further by fluorescence in situ hybridization to 9q34, distal to the dopamine beta-hydroxylase gene (DBH; 223360). The mapping position was confirmed by PCR on a panel of translocation hybrids. By pairwise hybridization of an RXRA cosmid and reference markers in fluorescence in situ hybridization, Almasan et al. (1994) refined the localization to 9q34.3.
Using RFLVs in interspecific backcross mice, Hoopes et al. (1992) mapped mouse genomic loci Rxra, Rxrb (180246), and Rxrg (180247) to chromosome 2 near the centromere, to the H-2 region of chromosome 17, and to distal chromosome 1 in tight linkage with the Pbx (176310) gene, respectively.
Dyson et al. (1995) demonstrated that RXRA -/- embryos produced by gene targeting display embryonic heart failure that initially manifests itself as a decrease in ventricular contractile function. The dysfunction is progressive in the ventricular chamber, while atrial structure and function remain relatively intact. Evidence of atrioventricular conduction blocks suggested that an RXR-alpha-dependent pathway may be required for normal development of the ventricular conduction system. In situ analysis of chamber-specific myosin light chain-2 demonstrated normal ventricular specification of the ventricular type in the RXR-alpha -/- embryonic heart, while the atrial type was persistently expressed in the ventricular chamber. Thus, the maturation of ventricular muscle cells appeared to be arrested. The mice displayed generalized edema, ventricular chamber hypoplasia, and muscular septal defects, and died at embryonic day 15. Dyson et al. (1995) hypothesized that retinoic acid provides a critical signal mediated through the RXR-alpha pathway that is required to allow progression of development of the ventricular region of the heart from its early atrium-like form to the thick-walled adult ventricle.
From a study of embryos heterozygous and homozygous for RXR-alpha deficiency generated by gene targeting, Gruber et al. (1996) concluded that RXR-alpha has a role in maintaining normal cardiac morphogenesis. In addition, their findings suggested that a relative deficiency in RXR-alpha or molecules downstream in its signaling pathway may represent congenital heart disease-susceptibility genes.
A large number of physiologic processes in the adult liver are regulated by nuclear receptors that require heterodimerization with RXRs. Wan et al. (2000) used cre-mediated recombination to disrupt the mouse Rxra gene specifically in hepatocytes. Although such mice were viable, molecular and biochemical parameters indicated that every one of the examined metabolic pathways in the liver, namely those mediated by Rxr heterodimerization with Ppara (PPARA; 170998), Car-beta (NR1I3; 603881), Pxr (NR1I2; 603065), Lxra (NR1H3; 602423), and Fxr (NR1H4; 603826), was compromised in the absence of Rxra. The authors stated that their data demonstrate the presence of a complex circuitry in which Rxra is integrated into a number of diverse physiologic pathways as a common regulatory component of cholesterol, fatty acid, bile acid, steroid, and xenobiotic metabolism and homeostasis.
In an elegant series of experiments designed to elucidate the effect of RXR activation on cholesterol balance, Repa et al. (2000) treated animals with the rexinoid LG268. Animals treated with rexinoid exhibited marked changes in cholesterol balance, including inhibition of cholesterol absorption and repressed bile acid synthesis. Studies with receptor-selective agonists revealed that oxysterol receptors (LXRs) and the bile acid receptor FXR are the RXR heterodimeric partners that mediate these effects by regulating expression of the reverse-cholesterol transporter ABC1 (600046) and the rate-limiting enzyme of bile acid synthesis CYP7A1 (118455), respectively. These RXR heterodimers serve as key regulators in cholesterol homeostasis by governing reverse cholesterol transport from peripheral tissues, bile acid synthesis in liver, and cholesterol absorption in intestine. Activation of RXR/LXR heterodimers inhibits cholesterol absorption by upregulation of ABC1 expression in the small intestine. Activation of RXR/FXR heterodimers represses CYP7A1 expression and bile acid production, leading to a failure to solubilize and absorb cholesterol. Studies have shown that RXR/FXR-mediated repression of CYP7A1 is dominant over RXR/LXR-mediated induction of CYP7A1, which explains why the rexinoid represses rather than activates CYP7A1 (Lu et al., 2000). Activation of the LXR signaling pathway results in the upregulation of ABC1 in peripheral cells, including macrophages, to efflux free cholesterol for transport back to the liver through high density lipoprotein, where it is converted to bile acids by the LXR-mediated increase in CYP7A1 expression. Secretion of biliary cholesterol in the presence of increased bile acid pools normally results in enhanced reabsorption of cholesterol; however, with the increased expression of ABC1 and efflux of cholesterol back into the lumen, there is a reduction in cholesterol absorption and net excretion of cholesterol and bile acid. Rexinoids therefore offer a novel class of agents for treating elevated cholesterol.
Li et al. (2000) developed an efficient technique to create spatiotemporally controlled somatic mutations of the Rxr-alpha gene in the mouse. Li et al. (2000) used tamoxifen-inducible Cre-ER(T) recombinases to ablate RXR-alpha selectively in adult mouse keratinocytes. In 6 to 7 weeks after the first tamoxifen treatment, alopecia developed in the ventral region of pro-mutant mice. At 12 to 16 weeks after treatment, large regions of ventral skin and smaller regions of dorsal skin were hairless. Cysts became visible under the skin surface and these enlarged and spread all over the body with time. At 16 weeks after treatment, hairless regions showed hair follicle degeneration, resulting in utriculi and dermal cysts. Keratin 6 (148041), which is usually expressed only in hair follicle outer root sheath, was also expressed in hyperproliferative interfollicular epidermis, indicating abnormal keratinocyte terminal differentiation. All abnormalities were less severe, and/or appeared later, in males than in females. Li et al. (2000) found that RXR-beta (180246) expression in adult skin is several-fold higher in males than in females. Study of tamoxifen-treated RXR-alpha/RXR-beta compound mutants demonstrated that RXR-beta can partially compensate for a loss of RXR-alpha function. Also, in accordance with a larger amount of RXR-beta in adult male skin, the functional redundancy was more pronounced in males than in females, as RXR-alpha/beta double mutant males and females were similarly affected, unlike the single mutants.
De Urquiza et al. (2000) identified docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid that is highly enriched in the adult mammalian brain, as the natural ligand for the retinoic X receptor in mouse brain.
Claudel et al. (2001) analyzed the effects of activation of RXR and some of its heterodimers in apolipoprotein E (107741)-null mice, a well-established animal model of atherosclerosis. An RXR agonist drastically reduced the development of atherosclerosis. In addition, a ligand for the peroxisome proliferator-activated receptor PPAR-gamma and a dual agonist of both PPAR-alpha and PPAR-gamma had moderate inhibitory effects. Both RXR and LXR agonists induced ATP-binding cassette protein-1 (ABC1) expression and stimulated ABC1-mediated cholesterol efflux from macrophages from wildtype but not from LXRA/LXRB (600380) double homozygous knockout mice. Hence, activation of ABC1-mediated cholesterol efflux by the RXR/LXR heterodimer may contribute to the beneficial effects of rexinoids on atherosclerosis and warrant further evaluation of RXR/LXR agonists in prevention and treatment of atherosclerosis.
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