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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Available from: Yacir Benomar, Oct 08, 2015
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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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    • "RXRα has the typical structure of nuclear receptor, including an N-terminal region, a central DNA-binding domain (DBD), and a C-terminal ligand-binding domain (LBD) (de Lera et al., 2007). The unique property of RXRα among nuclear receptors lies in its ability to form heterodimers with many other nuclear receptors such as retinoic acid receptors (RARs) and peroxisome proliferator-activated receptors (PPARs) (Lefebvre et al., 2010; Evans and Mangelsdorf, 2014). Like other nuclear receptors, RXRα has important genomic functions mainly through its binding to responding DNA elements to regulate target gene transcription (Tang and Gudas, 2011; Evans and Fan Chen, Jiebo Chen and Jiacheng Lin have contributed equally to this work. "
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    ABSTRACT: Retinoid X receptor α (RXRα) and its N-terminally truncated version tRXRα play important roles in tumorigenesis, while some RXRα ligands possess potent anti-cancer activities by targeting and modulating the tumorigenic effects of RXRα and tRXRα. Here we describe NSC-640358 (N-6), a thiazolyl-pyrazole derived compound, acts as a selective RXRα ligand to promote TNFα-mediated apoptosis of cancer cell. N-6 binds to RXRα and inhibits the transactivation of RXRα homodimer and RXRα/TR3 heterodimer. Using mutational analysis and computational study, we determine that Arg316 in RXRα, essential for 9-cis-retinoic acid binding and activating RXRα transactivation, is not required for antagonist effects of N-6, whereas Trp305 and Phe313 are crucial for N-6 binding to RXRα by forming extra π-π stacking interactions with N-6, indicating a distinct RXRα binding mode of N-6. N-6 inhibits TR3-stimulated transactivation of Gal4-DBD-RXRα-LBD by binding to the ligand binding pocket of RXRα-LBD, suggesting a strategy to regulate TR3 activity indirectly by using small molecules to target its interacting partner RXRα. For its physiological activities, we show that N-6 strongly inhibits tumor necrosis factor α (TNFα)-induced AKT activation and stimulates TNFα-mediated apoptosis in cancer cells in an RXRα/tRXRα dependent manner. The inhibition of TNFα-induced tRXRα/p85α complex formation by N-6 implies that N-6 targets tRXRα to inhibit TNFα-induced AKT activation and to induce cancer cell apoptosis. Together, our data illustrate a new RXRα ligand with a unique RXRα binding mode and the abilities to regulate TR3 activity indirectly and to induce TNFα-mediated cancer cell apoptosis by targeting RXRα/tRXRα.
    Protein & Cell 07/2015; 6(9). DOI:10.1007/s13238-015-0178-9 · 3.25 Impact Factor
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