Retinoid X receptors: Common heterodimerization partners with distinct functions

Université du Droit et de la Santé de Lille - Nord de France.
Trends in Endocrinology and Metabolism (Impact Factor: 9.39). 11/2010; 21(11):676-83. DOI: 10.1016/j.tem.2010.06.009
Source: PubMed


Retinoid X receptors (RXRs) have been implicated in a diversity of cellular processes ranging from cellular proliferation to lipid metabolism. These pleiotropic effects stem not only from the ability of RXRs to dimerize with diverse nuclear receptors, which exert transcriptional control on specific aspects of cell biology, but also because binding of RXR ligands to heterodimers can stimulate transcriptional activation by RXR partner receptors. This signaling network is rendered more complex by the existence of different RXR isotypes (RXRα, RXRβ, RXRγ) with distinct properties that thereby modulate the transcriptional activity of RXR-containing heterodimers. This review discusses the emerging roles of RXR isotypes in the RXR signaling network and possible implications for our understanding of nuclear receptor biology and pharmacology.

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    • "The retinoid x receptors (RXRí µí»¼, í µí»½, and í µí»¾) form heterodimers with a subclass of nuclear receptors (NRs) that include PPARs, LXRs, FXRs, PXRs, RARs, CAR, TR, and VDR to cooperatively modulate gene expression [1] [2]. These heterodimers can be classified as permissive, whereby agonists for either heterodimer partner can activate gene expression, or nonpermissive for which RXR agonists alone have no effect on transcriptional activity but can synergistically induce hyperactivation with partner agonists [3] [4]. "
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    ABSTRACT: The retinoid x receptors (RXRs) are the pharmacological target of Bexarotene, an antineoplastic agent indicated for the treatment of cutaneous T cell lymphoma (CTCL). The RXRs form heterodimers with several nuclear receptors (NRs), including peroxisome proliferator-activated receptor gamma (PPARγ), to regulate target gene expression through cooperative recruitment of transcriptional machinery. Here we have applied hydrogen/deuterium exchange (HDX) mass spectrometry to characterize the effects of Bexarotene on the conformational plasticity of the intact RXRα:PPARγ heterodimer. Interestingly, addition of Bexarotene to PPARγ in the absence of RXRα induced protection from solvent exchange, suggesting direct receptor binding. This observation was confirmed using a competitive binding assay. Furthermore, Bexarotene functioned as a PPARγ antagonist able to alter rosiglitazone induced transactivation in a cell based promoter:reporter transactivation assay. Together these results highlight the complex polypharmacology of lipophilic NR targeted small molecules and the utility of HDX for identifying and characterizing these interactions.
    PPAR Research 10/2015; 2015(4):254560. DOI:10.1155/2015/254560 · 1.64 Impact Factor
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    • "Specifically, previous work by Schadt et al. (2008) reported that rs1981429 might function as a trans-eQTL SNP associated with the expression of the Retinoic acid receptor-gamma (RXRG) gene expression in the liver of Caucasians. RXRG encodes a member of the RXR nuclear receptors that function as metabolic regulators to control a variety of physiological processes (Lefebvre et al., 2010). For example, RXR heterodimerizes with the 1,25-dihydroxyvitamin D-activated vitamin D receptor (VDR) to stimulate the expression of genes responsible for vitamin D-induced phenotypes (Pike and Meyer, 2010 "
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    ABSTRACT: Evidences from model systems and humans have suggested that genetic alterations in cell-ECM interactions and matrix-mediated cellular signaling cascades impact different aspects of metabolism and thereby life span. In this frame, a genetic variant (rs1981429) in the SDC4 gene encoding for syndecan-4, a central mediator of cell adhesion, has been associated with body composition in children and coronary artery disease in middle-age subjects. In order to test the hypothesis that SDCs might affect life span by affecting metabolic endophenotypes, 11 SNPs within the SDC4 gene were tested for association with longevity in a cohort of 64-107 aged individuals. We then determined whether the longevity-associated SNPs were correlated with metabolic parameters in the age group 64-85 years. RobustSNP association tests showed that rs1981429 was negatively associated with longevity (Theop = 0.028), but also with high levels of triglyceride (Theop = 0.028) and low levels of low-density lipoprotein-cholesterol (LDL-C) (Theop = 0.009). On the other hand, rs2251252 was found to be positively correlated with longevity (Theop = 0.018) and high LDL-C (Theop = 0.022). On the whole, our results suggest that SDC4 alleles affect lipid profile in elderly subjects and may in part mediate the link between LDL-C and longevity. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Mechanisms of ageing and development 08/2015; 150. DOI:10.1016/j.mad.2015.08.003 · 3.40 Impact Factor
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    • "Regarding the RXRs, their sequence is divided into several regions, which possess the same inter-type domain conservation as RARs [16] [17]. The RXRs are encoded by three distinct genes located on the human chromosomes 9 (RXRA, also known as NR2B1), 6 (RXRB, NR2B2), 1 (RXRG, NR2B3), and the mouse chromosomes 2, 17 and 1 [18] [19]. The human RXRα gene has 10 conserved exons but not a typical TATA transcription "
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    ABSTRACT: The nuclear retinoic acid receptor may play a critical role in the process of lung carcinogenesis. Alteration or loss of nuclear retinoic acid receptors (RARs) has been associated with progression in premalignant and malignant tissues and it is associated with malignant transformation in human cells. Vitamin A derivates, such as retinoic acid, have emerged as adjuvant to therapy in several types of cancer with favorable effects. Retinoic acid regulates the expression of target genes through the binding and activation of RARs, inhibiting growth proliferation. Diverse studies have evaluated different retinoids alone or in combination with chemotherapy in lung cancer, from which results have been controversial with benefits observed only in the subpopulation with high levels of triglycerides. Additionally, several large randomized trials using retinoids to prevent tobacco-related cancer have failed; due to the latter the use of retinoids in clinical trials remains controversial. However they could reduce the risk of cancer development in non-smokers. There is evidence that retinoids have different effects on lung cancer; still the identification of biomarkers could determinate their benefits as preventive or therapy agents. This review describes the RAR alterations during the development of Non-Small Cell Lung Cancer and sets out the importance of several cancer treatments with retinoid compounds.
    Journal of Cancer Therapy 08/2015; 6:648-664. DOI:10.4236/jct.2015.68072
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