Journal articles on the topic 'RXRs'
To see the other types of publications on this topic, follow the link: RXRs.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'RXRs.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Yagishita, Naoko, Yoko Yamamoto, Tatsuya Yoshizawa, Keisuke Sekine, Yoshikatsu Uematsu, Hisashi Murayama, Yumiko Nagai, et al. "Aberrant Growth Plate Development in VDR/RXRγ Double Null Mutant Mice." Endocrinology 142, no. 12 (December 1, 2001): 5332–41. http://dx.doi.org/10.1210/endo.142.12.8544.
Full textAbstract:
Abstract VDR forms heterodimers with one of three RXRs, RXRα, RXRβ, and RXRγ, and it is thought that RXR ligands can also modulate the trans-activation function of VDR/RXR heterodimers. In the present study we generated VDR/RXRγ double null mutant mice to examine the convergent actions of vitamin D and vitamin A signaling and to explore the possibility of a functionally redundant VDR. Although RXRγ−/− mice exhibited no overt abnormalities, VDR−/−/RXRγ−/− mice appeared similar to VDR−/− mice, showing features typical of vitamin D-dependent rickets type II, including growth retardation, impaired bone formation, hypocalcemia, and alopecia. However, compared to VDR−/− mice, growth plate development in VDR−/−/RXRγ−/− mutant mice was more severely impaired. Normalizing mineral ion homeostasis through dietary supplementation with high calcium and phosphorous effectively prevented rachitic abnormalities, except for disarranged growth plates in VDR−/−/RXRγ−/− mutant mice, and alopecia in both VDR−/− and VDR−/−/RXRγ−/− mutant mice. Histological analysis of VDR−/−/RXRγ−/− growth plates revealed that development of the hypertrophic chondrocytes was selectively impaired. Thus, our findings indicated that the combined actions of VDR- and RXRγ-mediated signals are essential for the normal development of growth plate chondrocytes, and raised the possibility that a functionally redundant VDR is present on chondrocytes as a heterodimer with RXRγ.
2
Dollé, Pascal. "Developmental expression of retinoic acid receptors (RARs)." Nuclear Receptor Signaling 7, no. 1 (January 2009): nrs.07006. http://dx.doi.org/10.1621/nrs.07006.
Full textAbstract:
Here, I review the developmental expression features of genes encoding the retinoic acid receptors (RARs) and the ‘retinoid X’ or rexinoid receptors (RXRs). The first detailed expression studies were performed in the mouse over two decades ago, following the cloning of the murine Rar genes. These studies revealed complex expression features at all stages of post-implantation development, one receptor gene (Rara) showing widespread expression, the two others (Rarb and Rarg) with highly regionalized and/or cell type-specific expression in both neural and non-neural tissues. Rxr genes also have either widespread (Rxra, Rxrb), or highly-restricted (Rxrg) expression patterns. Studies performed in zebrafish and Xenopus demonstrated expression of Rar and Rxr genes (both maternal and zygotic), at early pre-gastrulation stages. The eventual characterization of specific enzymes involved in the synthesis of retinoic acid (retinol/retinaldehyde dehydrogenases), or the triggering of its catabolism (CYP26 cytochrome P450s), all of them showing differential expression patterns, led to a clearer understanding of the phenomenons regulated by retinoic acid signaling during development. Functional studies involving targeted gene disruptions in the mouse, and additional approaches such as dominant negative receptor expression in other models, have pinpointed the specific, versus partly redundant, roles of the RARs and RXRs in many developing organ systems. These pleiotropic roles are summarized hereafter in relationship to the receptors’ expression patterns.
3
Sugawara, Akira, Naoko Sanno, Nobuyuki Takahashi, R. Yoshiyuki Osamura, and Keishi Abe. "Retinoid X Receptors in the Kidney: Their Protein Expression and Functional Significance." Endocrinology 138, no. 8 (August 1, 1997): 3175–80. http://dx.doi.org/10.1210/endo.138.8.5351.
Full textAbstract:
Abstract Retinoid X receptors (RXRs) heterodimerize with 1,25-dihydroxyvitamin D3 (VD) receptor (VDR), and play important roles in VD-regulated transactivation. VD acts on many tissues including kidney for the regulation of calcium homeostasis. In the kidney, the expression of VDR in the tubular cells has been well studied. In contrast, little is known about the localization and the functional significance of RXRs there. In order to elucidate these questions, we first performed immunohistochemical analyses of rat kidney using isoform-specific antimouse RXR antibodies we have previously reported. Interestingly, all RXR isoforms, predominantly RXRα, mainly localized to the proximal and the distal tubules, but not to the glomeruli. The serial section staining using anti-VDR antibody showed the colocalization of RXRα and VDR in those tubular cells. In order to elucidate the functional significance of endogenous receptors in the tubular cells, we next performed transient transfection studies using the tubular-cell derived Madin-Darby bovine kidney cells, which express both endogenous VDR and RXR. We transfected a reporter plasmid containing direct repeat 3 (DR3) sequence, to which only RXR/VDR heterodimer can bind, and found that VD and 9-cis retinoic acid, as well as VD and RXR selective agonist LG100153, had an additive effect for the DR3 transactivation. Taken together, we speculate that endogenous RXRs co-localize with VDR, and coregulate VD-dependent genes in the tubular cells of the kidney as RXR/VDR heterodimer.
4
Di Martino, Orsola, Margaret Y. Ferris, Hadwiger Gayla, Haixia Niu, and John S. Welch. "Endogenous Retinoid X Receptor Ligands Act As Tumor Suppressors in MLL-AF9 Mouse Leukemia." Blood 134, Supplement_1 (November 13, 2019): 2677. http://dx.doi.org/10.1182/blood-2019-128869.
Full textAbstract:
Retinoid therapy transformed response and survival outcomes in acute promyelocytic leukemia (APL), but has demonstrated only modest activity in non-APL forms of acute myeloid leukemia (AML). The retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are ligand-activated transcription factors that influence hematopoietic stem cell self-renewal and differentiation. In normal hematopoiesis, RARA and RXRA are dynamically regulated during myeloid maturation, with highest expression in mature neutrophils. In acute myeloid leukemia (AML) RARA and RXRA have parallel expression among AML subtypes, with the highest expression in M4/M5 myelomonocytic and monocytic subtypes. Using a murine reporter assay, we found that natural RXRA ligands, but not RARA ligands, were present in vivo in primary mouse myelomonocytic leukemia cells (derived with an MLL-AF9 retrovirus) and acted as tumor suppressors. RXR ligands were absent in erythroleukemia (derived with TLS-ERG) or T-cell leukemia (derived with activated Notch1), suggesting the presence of natural RXRA ligands specifically in myelomonocytic leukemia. Moreover, we found that deletion of Rxra and Rxrb was naturally selected in MLL-AF9, but not in Notch1 or TLS-ERG leukemias, and that loss of Rxra and Rxrb accelerated leukemic growth. This suggests that Rxrs act as tumor suppressors, but only when exposed to natural ligands. In MLL-AF9 derived leukemia cells, pharmacologic treatment with single-agent retinoid led to modest growth inhibition due to non-permissive activity of the RARA:RXR heterodimer, whereas concurrent activation of both RARA, with all-trans retinoic acid (a pan-RAR ligand), and RXR, by bexarotene (a pan-RXR ligand), enabled efficient co-repressor release and synergistic leukemic apoptosis. We observed that co-repressors release (SMRT/NCoR) from the RARA:RXRA heterodimer was specifically associated with RARA activation, whereas growth inhibition required RXR binding, and this occurred through apoptosis rather than maturation. Generating a series of RXRA mutant proteins we demonstrated the active contribution of RXRA to the activity of the RARA:RXRA heterodimer, specifically requiring the activation domains (AF1 and AF2) and the ability to recruit co-activator to the RXRA element. Finally, we observed a significant dose-dependent effect of combination ATRA and bexarotene treatment in in vivo in MLL-AF9 leukemic mice with a striking reduction in the tumor burden of treated mice compared to the control cohort. These data provide a strategy for clinical retinoid therapies in leukemias beyond acute promyelocytic leukemia and provide a mechanism for integrating retinoid therapy into future clinical trials. Disclosures No relevant conflicts of interest to declare.
5
Räuber, Saskia, Maximilian Fischer, Denise Messerer, Vanessa Wimmler, Kumaraswami Konda, Andrei Todica, Michael Lorenz, Anna Titova, Christian Schulz, and Tobias Weinberger. "Modulation of Rxrα Expression in Mononuclear Phagocytes Impacts on Cardiac Remodeling after Ischemia-Reperfusion Injury." Biomedicines 10, no. 6 (May 30, 2022): 1274. http://dx.doi.org/10.3390/biomedicines10061274.
Full textAbstract:
Retinoid X receptors (RXRs), as members of the steroid/thyroid hormone superfamily of nuclear receptors, are crucial regulators of immune response during health and disease. RXR subtype expression is dependent on tissue and cell type, RXRα being the relevant isoform in monocytes and macrophages. Previous studies have assessed different functions of RXRs and positive implications of RXR agonists on outcomes after ischemic injuries have been described. However, the impact of a reduced Rxrα expression in mononuclear phagocytes on cardiac remodeling after myocardial infarction (MI) has not been investigated to date. Here, we use a temporally controlled deletion of Rxrα in monocytes and macrophages to determine its role in ischemia-reperfusion injury. We show that reduced expression of Rxrα in mononuclear phagocytes leads to a decreased phagocytic activity and an accumulation of apoptotic cells in the myocardium, reduces angiogenesis and cardiac macrophage proliferation in the infarct border zone/infarct area, and has an impact on monocyte/macrophage subset composition. These changes are associated with a greater myocardial defect 30 days after ischemia/reperfusion injury. Overall, the reduction of Rxrα levels in monocytes and macrophages negatively impacts cardiac remodeling after myocardial infarction. Thus, RXRα might represent a therapeutic target to regulate the immune response after MI in order to improve cardiac remodeling.
6
Negro-Vilar, A., U. Gatzemeier, R. Ramlau, S. L. Sun, R. Negro-Vilar, T. Hermann, J. K. Zhang, and Z. Dziewanowska. "Biomarker correlates of survival in NSCLC: Role of RXRβ and PPARγ in mediating bexarotene impact on patient survival." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 7227. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.7227.
Full textAbstract:
7227 Background: Bexarotene is a selective modulator of retinoid X nuclear receptors (RXRs), which form heterodimers with many other nuclear receptors playing a critical role in cell growth, differentiation, and apoptosis. Loss of RXRs is seen in many advanced tumors, including NSCLC and higher RXR levels in NSCLC lung biopsies (stages I-III) have been correlated with longer overall survival. Two large first line NSCLC Phase III trials reported at ASCO 2005 (SPIRIT I and II) showed that while no benefit in overall survival was seen adding bexarotene to two chemo regimens, a large (36%) subpopulation of patients in both trials that had high grade hypertriglyceridemia in response to bexarotene had significantly longer survival. A retrospective analysis was conducted to evaluate the baseline characteristics of these patients and to examine the level of expression of RXR and one of its partners (PPARγ) in lung tumor tissue biopsies obtained from a subgroup of patients in both studies. Methods: RXRs (α,β,γ) and PPARγ expression levels in lung tumor tissue from patients in SPIRIT I and II trials (stage IIIB/IV) taken prior to study entry were assessed by Q-PCR analysis of RNA isolated from microdissected lung tumor tissue biopsies. Cox regression and Kaplan-Meier survival estimation were used for statistical evaluations. Results: In an initial subset of 41 patients, RXRβ expression in lung tumor showed positive correlation with survival. High RXRβ = longer survival (median survival 438 days), low RXR shorter (MS = 317). Treatment with bexarotene increased the differences (RXRβ Hi, MS = 627 days; RXRβ low = 211 days). PPARγ showed a negative correlation with survival and those patients with RXRβ Hi/PPARγ low ratios had the longest MS (627 days vs. 226 days for the RXRβ low/PPARγ high group), a difference that was magnified by bexarotene treatment. Conclusions: RXRβ expression level correlates with a positive survival in late stage NSCLC while PPARγ shows negative correlation. Bexarotene treatment enhances the survival differences, supporting an involvement of triglyceride and lipid metabolism as regulated by these two key nuclear receptors in the longer survival seen in the 215 patients in the high triglyceride subgroup. [Table: see text]
7
Vernet, Nadège, Christine Dennefeld, Cécile Rochette-Egly, Mustapha Oulad-Abdelghani, Pierre Chambon, Norbert B. Ghyselinck, and Manuel Mark. "Retinoic Acid Metabolism and Signaling Pathways in the Adult and Developing Mouse Testis." Endocrinology 147, no. 1 (January 1, 2006): 96–110. http://dx.doi.org/10.1210/en.2005-0953.
Full textAbstract:
As a first step in investigating the role of retinoic acid (RA) in mouse testis, we analyzed the distribution pattern of the enzymes involved in vitamin A storage (lecithin:retinol acyltransferase), RA synthesis (β-carotene 15,15′-monoxygenase and retinaldehyde dehydrogenases) and RA degradation (cytochrome P450 hydroxylases) as well as those of all isotypes of receptors transducing the RA signal [RA receptors (RARs) and rexinoid receptors (RXRs)]. Our data indicate that in adult testis 1) cytochrome P450 hydroxylase enzymes may generate in peritubular myoid cells a catabolic barrier that prevents circulating RA and RA synthesized by Leydig cells to enter the seminiferous epithelium; 2) the compartmentalization of RA synthesis within this epithelium may modulate, through paracrine mechanisms, the coupling between spermatogonia proliferation and spermatogenesis; 3) retinyl esters synthesized in round spermatids by lecithin:retinol acyltransferase may be transferred and stored in Sertoli cells, in the form of adipose differentiation-related protein-coated lipid droplets. We also show that RARα and RXRβ are confined to Sertoli cells, whereas RARγ is expressed in spermatogonia and RARβ, RXRα, and RXRγ are colocalized in step 7–8 spermatids. Correlating these expression patterns with the pathological phenotypes generated in response to RAR and RXR mutations and to postnatal vitamin A deficiency suggests that spermiation requires RXRβ/RARα heterodimers in Sertoli cells, whereas spermatogonia proliferation involves, independently of RXR, two distinct RAR-mediated signaling pathways in both Sertoli cells and spermatogonia. Our data also suggest that the involvement of RA in testis development starts when primary spermatogonia first appear.
8
Davis, K. D., T. J. Berrodin, J. E. Stelmach, J. D. Winkler, and M. A. Lazar. "Endogenous retinoid X receptors can function as hormone receptors in pituitary cells." Molecular and Cellular Biology 14, no. 11 (November 1994): 7105–10. http://dx.doi.org/10.1128/mcb.14.11.7105-7110.1994.
Full textAbstract:
Retinoids regulate gene transcription by interacting with both retinoic acid (RA) receptors (RARs) and retinoid X receptors (RXRs). Since unliganded RXRs can act as heterodimerization partners for RARs and other nuclear hormone receptors, it is unclear whether ligand binding by RXRs actually regulates the expression of naturally occurring genes. To address this issue, we synthesized the RXR-selective retinoid SR11237 and confirmed its specificity in transient transfection and proteolytic susceptibility assays before using it to assess the contribution of ligand-activated RXRs to retinoid action. Unlike RAR ligands, SR11237 did not increase endogenous RAR beta mRNA levels in F9 embryonal carcinoma cells, even though it activated transcription of an RXR-responsive reporter gene in these cells. Thus, it is likely that RARs mediate the induction of RAR beta gene expression by RA. In contrast, the RXR-specific ligand induced rat growth hormone mRNA in GH3 pituitary cells, indicating that the effects of RA on growth hormone gene expression at least in part involve ligand binding to endogenous RXRs in vivo. Our results indicate that in addition to serving as cofactors for other nuclear hormone receptors, endogenous RXRs can function as ligand-dependent regulators of gene expression, i.e., classical nuclear hormone receptors.
9
Davis, K. D., T. J. Berrodin, J. E. Stelmach, J. D. Winkler, and M. A. Lazar. "Endogenous retinoid X receptors can function as hormone receptors in pituitary cells." Molecular and Cellular Biology 14, no. 11 (November 1994): 7105–10. http://dx.doi.org/10.1128/mcb.14.11.7105.
Full textAbstract:
Retinoids regulate gene transcription by interacting with both retinoic acid (RA) receptors (RARs) and retinoid X receptors (RXRs). Since unliganded RXRs can act as heterodimerization partners for RARs and other nuclear hormone receptors, it is unclear whether ligand binding by RXRs actually regulates the expression of naturally occurring genes. To address this issue, we synthesized the RXR-selective retinoid SR11237 and confirmed its specificity in transient transfection and proteolytic susceptibility assays before using it to assess the contribution of ligand-activated RXRs to retinoid action. Unlike RAR ligands, SR11237 did not increase endogenous RAR beta mRNA levels in F9 embryonal carcinoma cells, even though it activated transcription of an RXR-responsive reporter gene in these cells. Thus, it is likely that RARs mediate the induction of RAR beta gene expression by RA. In contrast, the RXR-specific ligand induced rat growth hormone mRNA in GH3 pituitary cells, indicating that the effects of RA on growth hormone gene expression at least in part involve ligand binding to endogenous RXRs in vivo. Our results indicate that in addition to serving as cofactors for other nuclear hormone receptors, endogenous RXRs can function as ligand-dependent regulators of gene expression, i.e., classical nuclear hormone receptors.
10
Mascrez, Bénédicte, Manuel Mark, Wojciech Krezel, Valérie Dupé, Marianne LeMeur, Norbert B. Ghyselinck, and Pierre Chambon. "Differential contributions of AF-1 and AF-2 activities to the developmental functions of RXRα." Development 128, no. 11 (June 1, 2001): 2049–62. http://dx.doi.org/10.1242/dev.128.11.2049.
Full textAbstract:
We have engineered a mouse mutation that specifically deletes most of the RXRα N-terminal A/B region, which includes the activation function AF-1 and several phosphorylation sites. The homozygous mutants (RXRαaf1o), as well as compound mutants that further lack RXRβ and RXRγ, are viable and display a subset of the abnormalities previously described in RXRα-null mutants. In contrast, RXRαaf1o/RAR−/−(α, β or γ) compound mutants die in utero and exhibit a large array of malformations that nearly recapitulate the full spectrum of the defects that characterize the fetal vitamin A-deficiency (VAD) syndrome. Altogether, these observations indicate that the RXRα AF-1 region A/B is functionally important, although less so than the ligand-dependent activation function AF-2, for efficiently transducing the retinoid signal through RAR/RXRα heterodimers during embryonic development. Moreover, it has a unique role in retinoic acid-dependent involution of the interdigital mesenchyme. During early placentogenesis, both the AF-1 and AF-2 activities of RXRα, β and γ appear to be dispensable, suggesting that RXRs act as silent heterodimeric partners in this process. However, AF-2 of RXRα, but not AF-1, is required for differentiation of labyrinthine trophoblast cells, a late step in the formation of the placental barrier.
11
SCHACHTRUP, Christian, Tanja EMMLER, Bertram BLECK, Anton SANDQVIST, and Friedrich SPENER. "Functional analysis of peroxisome-proliferator-responsive element motifs in genes of fatty acid-binding proteins." Biochemical Journal 382, no. 1 (August 10, 2004): 239–45. http://dx.doi.org/10.1042/bj20031340.
Full textAbstract:
Retinoic acids and long-chain fatty acids are lipophilic agonists of nuclear receptors such as RXRs (retinoic X receptors) and PPARs (peroxisome-proliferator-activated receptors) respectively. These agonists are also ligands of intracellular lipid-binding proteins, which include FABPs (fatty acid-binding proteins). We reported previously that L (liver-type)-FABP targets fatty acids to the nucleus of hepatocytes and affects PPARα activation, which binds together with an RXR subtype to a PPRE (peroxisome-proliferator-responsive element). In the present study, we first determined the optimal combination of murine PPAR/RXR subtypes for binding to known murine FABP-PPREs and to those found by computer search and then tested their in vitro functionality. We show that all PPARs bind to L-FABP-PPRE, PPARα, PPARγ1 and PPARγ2 to A (adipocyte-type)-FABP-PPRE. All PPAR/RXR heterodimers transactivate L-FABP-PPRE, best are combinations of PPARα with RXRα or RXRγ. In contrast, PPARα heterodimers do not transactivate A-FABP-PPRE, best combinations are of PPARγ1 with RXRα and RXRγ, and of PPARγ2 with all RXR subtypes. We found that the predicted E (epidermal-type)- and H (heart-type)-FABP-PPREs are not activated by any PPAR/RXR combination without or with the PPAR pan-agonist bezafibrate. In the same way, C2C12 myoblasts transfected with promoter fragments of E-FABP and H-FABP genes containing putative PPREs are also not activated through stimulation of PPARs with bezafibrate applied to the cells. These results demonstrate that only PPREs of L- and A-FABP promoters are functional, and that binding of PPAR/RXR heterodimers to a PPRE in vitro does not necessarily predict transactivation.
12
Lavigne, Anne-Claire, Gabrielle Mengus, Yann-Gaël Gangloff, Jean-Marie Wurtz, and Irwin Davidson. "Human TAFII55 Interacts with the Vitamin D3 and Thyroid Hormone Receptors and with Derivatives of the Retinoid X Receptor That Have Altered Transactivation Properties." Molecular and Cellular Biology 19, no. 8 (August 1, 1999): 5486–94. http://dx.doi.org/10.1128/mcb.19.8.5486.
Full textAbstract:
ABSTRACT We have identified novel interactions between the human (h)TATA-binding protein-associated factor TAFII55 and the ligand-binding domains (LBDs) of the nuclear receptors for vitamin D3 (VDR) and thyroid hormone (TRα). Following expression in Cos cells, hTAFII55 interacts with the VDR and TRα LBDs in a ligand-independent manner whereas no interactions with the retinoid X receptors (RXRs) or with other receptors were observed. Deletion mapping indicates that hTAFII55 interacts with a 40-amino-acid region spanning α-helices H3 to H5 of the VDR and TRα LBDs but not with the equivalent highly related region of RXRγ. TAFII55 also interacts with chimeric receptors in which the H3-to-H5 region of RXRγ has been replaced with that of the VDR or TRα. Furthermore, replacement of two single amino acids of the RXRγ LBD with their VDR counterparts allows the RXRγ LBD to interact with hTAFII55 while the corresponding double substitution allows a much stronger interaction. In transfection experiments, the single mutated RXRγ LBDs activate transcription to fivefold higher levels than wild-type RXRγ while the double mutation activates transcription to a level comparable to that observed with the VDR. There is therefore a correlation between the ability of the modified RXRs to interact with hTAFII55 and transactivation. These results strongly suggest that the TAFII55 interactions with the modified RXR LBDs modulate transcriptional activation.
13
Lotan, Yair, Xiao C. Xu, Moshe Shalev, Reuben Lotan, Russell Williams, Thomas M. Wheeler, Timothy C. Thompson, and Dov Kadmon. "Differential Expression of Nuclear Retinoid Receptors in Normal and Malignant Prostates." Journal of Clinical Oncology 18, no. 1 (January 1, 2000): 116. http://dx.doi.org/10.1200/jco.2000.18.1.116.
Full textAbstract:
PURPOSE: To determine (1) whether nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are differentially expressed in normal and in cancerous human prostate tissues and (2) whether oral fenretinide therapy impacts the expression of these receptors in prostate cancer. PATIENTS AND METHODS: In situ hybridization with antisense riboprobes was used to probe for RAR and RXR transcripts in prostate tissues in a two-phased study: (1) expression of retinoid receptors in eight normal prostates was compared with their expression in 10 randomly picked radical prostatectomy specimens (group A); (2) expression of retinoid receptors was determined in 22 radical prostatectomy specimens from participants in a clinical study (group B). Twelve patients received oral fenretinide 200 mg/d, and 10 received placebo pills for 28 days before surgery. RESULTS: RARα, RARγ, RXRα, and RXRγ mRNAs were detected in most normal and cancerous prostates. In group A, RARβ mRNA was expressed in only four of 10 malignant prostates but was present in seven of eight benign prostates (P = .05). RXRβ mRNA was expressed in four of eight benign prostates and in zero of 10 malignant prostates (P = .023). In group B prostates, RARβ and RXRβ mRNAs were markedly reduced in all cancers and in the adjacent, nonmalignant tissue. There were no differences between receptor expression in the fenretinide-treated group and the placebo group. CONCLUSION: RARβ and RXRβ mRNAs are selectively lost in both prostate cancer and adjacent morphologically normal prostatic tissue, supporting the concept of a field of carcinogenesis. One month of oral fenretinide (200 mg/d) did not influence the expression of retinoid receptors in prostate cancer.
14
Wan, Yu-Jui Yvonne, Dahsing An, Yan Cai, Joyce J. Repa, Tim Hung-Po Chen, Monica Flores, Catherine Postic, et al. "Hepatocyte-Specific Mutation Establishes Retinoid X Receptor α as a Heterodimeric Integrator of Multiple Physiological Processes in the Liver." Molecular and Cellular Biology 20, no. 12 (June 15, 2000): 4436–44. http://dx.doi.org/10.1128/mcb.20.12.4436-4444.2000.
Full textAbstract:
ABSTRACT A large number of physiological processes in the adult liver are regulated by nuclear receptors that require heterodimerization with retinoid X receptors (RXRs). In this study, we have usedcre-mediated recombination to disrupt the mouse RXRα gene specifically in hepatocytes. Although such mice are viable, molecular and biochemical parameters indicate that every one of the examined metabolic pathways in the liver (mediated by RXR heterodimerization with PPARα, CARβ, PXR, LXR, and FXR) is compromised in the absence of RXRα. These data demonstrate the presence of a complex circuitry in which RXRα is integrated into a number of diverse physiological pathways as a common regulatory component of cholesterol, fatty acid, bile acid, steroid, and xenobiotic metabolism and homeostasis.
15
Lehmann, J. M., X. K. Zhang, G. Graupner, M. O. Lee, T. Hermann, B. Hoffmann, and M. Pfahl. "Formation of retinoid X receptor homodimers leads to repression of T3 response: hormonal cross talk by ligand-induced squelching." Molecular and Cellular Biology 13, no. 12 (December 1993): 7698–707. http://dx.doi.org/10.1128/mcb.13.12.7698-7707.1993.
Full textAbstract:
Thyroid hormone receptors (TRs) form heterodimers with retinoid X receptors (RXRs). Heterodimerization is required for efficient TR DNA binding to most response elements and transcriptional activation by thyroid hormone. RXRs also function as auxiliary proteins for several other receptors. In addition, RXR alpha can be induced by specific ligands to form homodimers. Here we report that RXR-specific retinoids that induce RXR homodimers are effective repressors of the T3 response. We provide evidence that this repression by RXR-specific ligands occurs by sequestering of RXR from TR-RXR heterodimers into RXR homodimers. This ligand-induced squelching may represent an important mechanism by which RXR-specific retinoids and 9-cis retinoic acid mediate hormonal cross talk among a subfamily of nuclear receptors activated by structurally unrelated ligands.
16
Lehmann, J. M., X. K. Zhang, G. Graupner, M. O. Lee, T. Hermann, B. Hoffmann, and M. Pfahl. "Formation of retinoid X receptor homodimers leads to repression of T3 response: hormonal cross talk by ligand-induced squelching." Molecular and Cellular Biology 13, no. 12 (December 1993): 7698–707. http://dx.doi.org/10.1128/mcb.13.12.7698.
Full textAbstract:
Thyroid hormone receptors (TRs) form heterodimers with retinoid X receptors (RXRs). Heterodimerization is required for efficient TR DNA binding to most response elements and transcriptional activation by thyroid hormone. RXRs also function as auxiliary proteins for several other receptors. In addition, RXR alpha can be induced by specific ligands to form homodimers. Here we report that RXR-specific retinoids that induce RXR homodimers are effective repressors of the T3 response. We provide evidence that this repression by RXR-specific ligands occurs by sequestering of RXR from TR-RXR heterodimers into RXR homodimers. This ligand-induced squelching may represent an important mechanism by which RXR-specific retinoids and 9-cis retinoic acid mediate hormonal cross talk among a subfamily of nuclear receptors activated by structurally unrelated ligands.
17
Sharma, Samridhi, Ting Shen, Nitin Chitranshi, Veer Gupta, Devaraj Basavarajappa, Soumalya Sarkar, Mehdi Mirzaei, et al. "Retinoid X Receptor: Cellular and Biochemical Roles of Nuclear Receptor with a Focus on Neuropathological Involvement." Molecular Neurobiology 59, no. 4 (January 11, 2022): 2027–50. http://dx.doi.org/10.1007/s12035-021-02709-y.
Full textAbstract:
AbstractRetinoid X receptors (RXRs) present a subgroup of the nuclear receptor superfamily with particularly high evolutionary conservation of ligand binding domain. The receptor exists in α, β, and γ isotypes that form homo-/heterodimeric complexes with other permissive and non-permissive receptors. While research has identified the biochemical roles of several nuclear receptor family members, the roles of RXRs in various neurological disorders remain relatively under-investigated. RXR acts as ligand-regulated transcription factor, modulating the expression of genes that plays a critical role in mediating several developmental, metabolic, and biochemical processes. Cumulative evidence indicates that abnormal RXR signalling affects neuronal stress and neuroinflammatory networks in several neuropathological conditions. Protective effects of targeting RXRs through pharmacological ligands have been established in various cell and animal models of neuronal injury including Alzheimer disease, Parkinson disease, glaucoma, multiple sclerosis, and stroke. This review summarises the existing knowledge about the roles of RXR, its interacting partners, and ligands in CNS disorders. Future research will determine the importance of structural and functional heterogeneity amongst various RXR isotypes as well as elucidate functional links between RXR homo- or heterodimers and specific physiological conditions to increase drug targeting efficiency in pathological conditions.
18
MacDonald, P. N., D. R. Dowd, S. Nakajima, M. A. Galligan, M. C. Reeder, C. A. Haussler, K. Ozato, and M. R. Haussler. "Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene." Molecular and Cellular Biology 13, no. 9 (September 1993): 5907–17. http://dx.doi.org/10.1128/mcb.13.9.5907-5917.1993.
Full textAbstract:
The vitamin D receptor (VDR) binds the vitamin D-responsive element (VDRE) as a heterodimer with an unidentified receptor auxiliary factor (RAF) present in mammalian cell nuclear extracts. VDR also interacts with the retinoid X receptors (RXRs), implying that RAF may be related to the RXRs. Here we demonstrate that highly purified HeLa cell RAF contained RXR beta immunoreactivity and that both activities copurified and precisely coeluted in high-resolution hydroxylapatite chromatography. Furthermore, an RXR beta-specific antibody disrupted VDR-RAF-VDRE complexes in mobility shift assays. These data strongly indicate that HeLa RAF is highly related to or is identical to RXR beta. Consequently, the effect of the 9-cis retinoic acid ligand for RXRs was examined in 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]-activated gene expression systems. Increasing concentrations of 9-cis retinoic acid (1 nM to 1 microM) markedly reduced 1,25(OH)2D3-dependent accumulation of osteocalcin mRNA in osteoblast-like ROS 17/2.8 cells. All-trans retinoic acid also interfered with vitamin D responsiveness, but it was consistently less potent than the 9-cis isomer. Transient transfection studies revealed that attenuation by 9-cis retinoic acid was at the transcriptional level and was mediated through interactions at the osteocalcin VDRE. Furthermore, overexpression of both RXR beta and RXR alpha augmented 1,25(OH)2D3 responsiveness in transient expression studies. Direct analysis of VDRE binding in mobility shift assays demonstrated that heteromeric interactions between VDR and RXR were enhanced by 1,25(OH)2D3 and were not affected appreciably by 9-cis retinoic acid, except that inhibition was observed at high retinoid concentrations. These data suggest a regulatory mechanism for osteocalcin gene expression that involves 1,25(OH)2D3-induced heterodimerization of VDR and unliganded RXR. 9-cis retinoic acid may attenuate 1,25(OH)2D3 responsiveness by diverting RXRs away from VDR-mediated transcription and towards other RXR-dependent transcriptional pathways.
19
MacDonald, P. N., D. R. Dowd, S. Nakajima, M. A. Galligan, M. C. Reeder, C. A. Haussler, K. Ozato, and M. R. Haussler. "Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene." Molecular and Cellular Biology 13, no. 9 (September 1993): 5907–17. http://dx.doi.org/10.1128/mcb.13.9.5907.
Full textAbstract:
The vitamin D receptor (VDR) binds the vitamin D-responsive element (VDRE) as a heterodimer with an unidentified receptor auxiliary factor (RAF) present in mammalian cell nuclear extracts. VDR also interacts with the retinoid X receptors (RXRs), implying that RAF may be related to the RXRs. Here we demonstrate that highly purified HeLa cell RAF contained RXR beta immunoreactivity and that both activities copurified and precisely coeluted in high-resolution hydroxylapatite chromatography. Furthermore, an RXR beta-specific antibody disrupted VDR-RAF-VDRE complexes in mobility shift assays. These data strongly indicate that HeLa RAF is highly related to or is identical to RXR beta. Consequently, the effect of the 9-cis retinoic acid ligand for RXRs was examined in 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]-activated gene expression systems. Increasing concentrations of 9-cis retinoic acid (1 nM to 1 microM) markedly reduced 1,25(OH)2D3-dependent accumulation of osteocalcin mRNA in osteoblast-like ROS 17/2.8 cells. All-trans retinoic acid also interfered with vitamin D responsiveness, but it was consistently less potent than the 9-cis isomer. Transient transfection studies revealed that attenuation by 9-cis retinoic acid was at the transcriptional level and was mediated through interactions at the osteocalcin VDRE. Furthermore, overexpression of both RXR beta and RXR alpha augmented 1,25(OH)2D3 responsiveness in transient expression studies. Direct analysis of VDRE binding in mobility shift assays demonstrated that heteromeric interactions between VDR and RXR were enhanced by 1,25(OH)2D3 and were not affected appreciably by 9-cis retinoic acid, except that inhibition was observed at high retinoid concentrations. These data suggest a regulatory mechanism for osteocalcin gene expression that involves 1,25(OH)2D3-induced heterodimerization of VDR and unliganded RXR. 9-cis retinoic acid may attenuate 1,25(OH)2D3 responsiveness by diverting RXRs away from VDR-mediated transcription and towards other RXR-dependent transcriptional pathways.
20
Puzianowska-Kuznicka, M., S. Damjanovski, and Y. B. Shi. "Both thyroid hormone and 9-cis retinoic acid receptors are required to efficiently mediate the effects of thyroid hormone on embryonic development and specific gene regulation in Xenopus laevis." Molecular and Cellular Biology 17, no. 8 (August 1997): 4738–49. http://dx.doi.org/10.1128/mcb.17.8.4738.
Full textAbstract:
Tissue culture transfection and in vitro biochemical studies have suggested that heterodimers of thyroid hormone receptors (TRs) and 9-cis retinoic acid receptors (RXRs) are the likely in vivo complexes that mediate the biological effects of thyroid hormone, 3,5,3'-triiodothyronine (T3). However, direct in vivo evidence for such a hypothesis has been lacking. We have previously reported a close correlation between the coordinated expression of TR and RXR genes and tissue-dependent temporal regulation of organ transformations during Xenopus laevis metamorphosis. By introducing TRs and RXRs either individually or together into developing Xenopus embryos, we demonstrate here that RXRs are critical for the developmental function of TRs. Precocious expression of TRs and RXRs together but not individually leads to drastic, distinct embryonic abnormalities, depending upon the presence or absence of T3, and these developmental effects require the same receptor domains as those required for transcriptional regulation by TR-RXR heterodimers. More importantly, the overexpressed TR-RXR heterodimers faithfully regulate endogenous T3 response genes that are normally regulated by T3 only during metamorphosis. That is, they repress the genes in the absence of T3 and activate them in the presence of the hormone. On the other hand, the receptors have no effect on a retinoic acid (RA) response gene. Thus, RA- and T3 receptor-mediated teratogenic effects in Xenopus embryos occur through distinct molecular pathways, even though the resulting phenotypes have similarities.
21
Kizaki, M., MI Dawson, R. Heyman, E. Elster, R. Morosetti, S. Pakkala, DL Chen, et al. "Effects of novel retinoid X receptor-selective ligands on myeloid leukemia differentiation and proliferation in vitro." Blood 87, no. 5 (March 1, 1996): 1977–84. http://dx.doi.org/10.1182/blood.v87.5.1977.1977.
Full textAbstract:
Abstract The biologic effects of retinoids such as all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid on proliferation and differentiation of hematopoietic cells are mediated by binding and activating two distinct families of transcription factors: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). The RARs require heterodimerization with RXRs; in addition, RXRs can form homodimers, which can bind to DNA response elements that are either distinct or the same as those bound by the RAR/RXR heterodimers. Therefore, the two retinoid pathways provide sequences that are specific for effective DNA binding and activation of target genes. We have developed several series of novel synthetic retinoids that selectively interact with RXR/RXR homodimers and RAR/RXR heterodimers. We show here that SR11236 and SR11246, which are RXR-selective analogs, had little ability to inhibit clonal growth and induce differentiation of leukemic cells (HL- 60 cells and fresh acute myeloid leukemia cells). However, SR11249, SR11256, and LGD1069, which activated both RXR/RXR homodimers and RAR/RXR heterodimers, could inhibit clonal growth and induce differentiation of HL-60 cells as well as leukemic cells from patients, including those with acute promyelocytic leukemia (APL). This is similar to results observed with RAR/RXR-specific ligands. Interestingly, the combination of ATRA and either SR11249, SR11256, or LGD1069 showed synergistic effects in inducing differentiation of HL-60 cells. A retinoid (SR11238) with strong anti-AP-1 activity that did not activate the RARs and RXRs for gene transcription from the response element TREpal was inactive in our assay systems, suggesting that the antiproliferative effects of retinoids on leukemic cells is not mediated by inhibiting the AP-1 pathway. We conclude that the RAR/RXR pathway is more important than RXR/RXR pathway for differentiation and proliferation of acute myeloid leukemic cells, and certain retinoids or combination of retinoids with both RAR and RXR specificities may synergistically enhance the differentiation activity of ATRA, which may be relevant in several clinical situations.
22
Kizaki, M., MI Dawson, R. Heyman, E. Elster, R. Morosetti, S. Pakkala, DL Chen, et al. "Effects of novel retinoid X receptor-selective ligands on myeloid leukemia differentiation and proliferation in vitro." Blood 87, no. 5 (March 1, 1996): 1977–84. http://dx.doi.org/10.1182/blood.v87.5.1977.bloodjournal8751977.
Full textAbstract:
The biologic effects of retinoids such as all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid on proliferation and differentiation of hematopoietic cells are mediated by binding and activating two distinct families of transcription factors: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). The RARs require heterodimerization with RXRs; in addition, RXRs can form homodimers, which can bind to DNA response elements that are either distinct or the same as those bound by the RAR/RXR heterodimers. Therefore, the two retinoid pathways provide sequences that are specific for effective DNA binding and activation of target genes. We have developed several series of novel synthetic retinoids that selectively interact with RXR/RXR homodimers and RAR/RXR heterodimers. We show here that SR11236 and SR11246, which are RXR-selective analogs, had little ability to inhibit clonal growth and induce differentiation of leukemic cells (HL- 60 cells and fresh acute myeloid leukemia cells). However, SR11249, SR11256, and LGD1069, which activated both RXR/RXR homodimers and RAR/RXR heterodimers, could inhibit clonal growth and induce differentiation of HL-60 cells as well as leukemic cells from patients, including those with acute promyelocytic leukemia (APL). This is similar to results observed with RAR/RXR-specific ligands. Interestingly, the combination of ATRA and either SR11249, SR11256, or LGD1069 showed synergistic effects in inducing differentiation of HL-60 cells. A retinoid (SR11238) with strong anti-AP-1 activity that did not activate the RARs and RXRs for gene transcription from the response element TREpal was inactive in our assay systems, suggesting that the antiproliferative effects of retinoids on leukemic cells is not mediated by inhibiting the AP-1 pathway. We conclude that the RAR/RXR pathway is more important than RXR/RXR pathway for differentiation and proliferation of acute myeloid leukemic cells, and certain retinoids or combination of retinoids with both RAR and RXR specificities may synergistically enhance the differentiation activity of ATRA, which may be relevant in several clinical situations.
23
Kyakumoto, Seiko, Minoru Ota, and Nobuko Sato. "Inhibition of retinoic acid-inducible transcription by COUP-TFI in human salivary gland adenocarcinoma cell line HSG." Biochemistry and Cell Biology 77, no. 6 (December 1, 1999): 515–26. http://dx.doi.org/10.1139/o99-057.
Full textAbstract:
Human salivary gland adenocarcinoma cells (HSG) express nuclear receptors, all-trans-retinoic acid (at-RA) receptors (RARs), and retinoid X/9-cis-retinoic acid (9-c-RA) receptors (RXRs). In order to investigate whether the endogenous RARs or RXRs of HSG cells can induce transcription activation, the thymidine kinase promoter (TK)-driven luciferase reporter gene containing the retinoic acid response element (RARE), of RARβ, βRARE2-TK-Luc, was transfected into HSG cells and ligand-dependent transcription activation was examined. Luciferase activity of cell lysate increased by the treatment with either at-RA or 9-c-RA. Co-transfection of RARα and (or) RXRα-expression plasmids with the reporter gene enhanced the luciferase activity, suggesting that endogenous RARs and RXRs work as ligand-dependent transfactors in HSG cells. Reverse transcriptase - polymerase chain reaction analysis revealed that HSG cells express chicken ovalbumin upstream promoter - transcription factor I (COUP-TFI). Co-transfection of COUP-TFI-expression plasmid suppressed the at-RA-induced transcription activation of the reporter gene. Similar results were shown using a chromatin-integrated reporter gene system, using a stably transfected β-RARE2-TK-β-galactosidase (β-Gal) reporter gene. The at-RA-dependent increase in the β-Gal expression was completely inhibited by COUP-TFI. The transfection of antisense oligonucleotide of COUP-TFI squelched the RA-dependent growth inhibition induced by RAR-RXR heterodimers. Conclusively, RARs and RXRs of HSG cells are functional and play roles as transactivators in at-RA-sensitive processes such as the proliferation or differentiation of cells. COUP-TFI very likely regulates these processes by repressing the functions of these transactivators.Key words: retinoic acid receptor, retinoid X receptor, COUP-transcription factor (COUP-TF), retinoic acid response element.
24
Jones, B. B., C. K. Ohno, G. Allenby, M. B. Boffa, A. A. Levin, J. F. Grippo, and M. Petkovich. "New retinoid X receptor subtypes in zebra fish (Danio rerio) differentially modulate transcription and do not bind 9-cis retinoic acid." Molecular and Cellular Biology 15, no. 10 (October 1995): 5226–34. http://dx.doi.org/10.1128/mcb.15.10.5226.
Full textAbstract:
Retinoid X receptors (RXRs), along with retinoic acid (RA) receptors (RARs), mediate the effects of RA on gene expression. Three subtypes of RXRs (alpha, beta, and gamma) which bind to and are activated by the 9-cis stereoisomer of RA have been characterized. They activate gene transcription by binding to specific sites on DNA as homodimers or as heterodimers with RARs and other related nuclear receptors, including the vitamin D receptor, thyroid hormone receptors (TRs), and peroxisome proliferator-activated receptors. Two additional RXR subtypes (delta and epsilon) isolated from zebra fish cDNA libraries are described here; although both subtypes form DNA-binding heterodimers with RARs and TR, neither binds 9-cis RA, and both are transcriptionally inactive on RXR response elements. In cotransfection studies with TR, the delta subtype was found to function in a dominant negative manner, while the epsilon subtype had a slight stimulatory effect on thyroid hormone (T3)-dependent transcriptional activity. The discovery of these two novel receptors in zebra fish expands the functional repertoire of RXRs to include ligand-independent and dominant negative modulation of type II receptor function.
25
Kyakumoto, Seiko, Takayuki Nemoto, Nobuko Sato, and Minoru Ota. "Expression of retinoid X receptors and COUP-TFI in a human salivary gland adenocarcinoma cell line." Biochemistry and Cell Biology 75, no. 6 (December 1, 1997): 749–58. http://dx.doi.org/10.1139/o97-080.
Full textAbstract:
The growth of the adenocarcinoma cell line derived from human salivary gland (HSG) is regulated by all-trans-retinoic acid (t-RA), which binds to its specific receptor, retinoic acid receptors (RARs), located in the nucleus, and thereby transactivates target genes. In this study, we examined the binding characteristics of the nuclear extract of HSG cells to the retinoic acid response element (RARE) compared with those of in vitro translated RAR alpha and retinoid X receptor alpha (RXR alpha ), a heterodimeric partner of RAR alpha . Gel shift analysis using anti-RAR alpha and anti-RXR alpha antibodies revealed that the translated RAR alpha bound to RARE as a heterodimer with RXR alpha . In contrast, the binding of the nuclear extract of HSG cells to RARE showed a heterogenous pattern, suggesting the existence of several species of RXRs as well as RARs in the nuclei of HSG cells. We therefore tried to clone these putative RXRs by the polymerase chain reaction using degenerated oligonucleotide primers conserved across the RXR family. The DNA sequencing of the recombinant clones revealed the expression of RXR alpha and RXR beta . In addition, chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI), which is also an RXR family member, was cloned. To evaluate the transcriptional activity of RARs and RXRs endogenously expressed in HSG cells, we performed a transient transfection analysis. When HSG cells were transfected with a luciferase reporter plasmid containing two repeats of either the RARE of the RAR beta gene or that of cellular retinol-binding protein II gene, positioned upstream of a thymidine kinase promoter fused to the luciferase sequence, a 2-3-fold induction of luciferase activity was observed in both cases. These results suggest that RARs and RXRs endogenously expressed in HSG cells were transcriptionally active in vivo. Thus, our findings showed that RXR alpha , RXR beta , and COUP-TFI are expressed in HSG cells and suggest that these molecules function as heterodimeric partners of RARs and (or) competitive repressors for RAREs and are involved in cellular responses mediated by retinoids. Key words: retinoid X receptor, retinoic acid receptor, retinoic acid response element, COUP-transcription factor (COUP-TF).
26
Mark, Manuel, and Pierre Chambon. "Functions of RARs and RXRs in vivo: Genetic dissection of the retinoid signaling pathway." Pure and Applied Chemistry 75, no. 11-12 (January 1, 2003): 1709–32. http://dx.doi.org/10.1351/pac200375111709.
Full textAbstract:
Retinoids, the active metabolites of vitamin A, regulate complex gene networks involved in vertebrate morphogenesis, growth, cellular differentiation, and homeostasis. They are used for the treatment of skin disorders and as chemopreventive agents for certain cancers. Molecular biology and genetic studies performed during the last 15 years in vitro, using either acellular systems or transfected cells, have shown that retinoid actions are mediated through heterodimers between the 8 major RARα, β, and γ; isoforms and the 6 major RXRα, β and γ isoforms that belong to the nuclear receptor (NR) superfamily, and act as ligand-dependent transcriptional regulators. Furthermore, RXRs not only heterodimerize with RARs, but also with numerous other members of the NR superfamily. As in vitro studies are carried out under nonphysiological conditions, they only indicate what is possible, but not necessarily what is actually occurring in vivo. Therefore, mutations have been introduced by homologous recombination (HR) in F9 embryonal carcinoma (EC) cells, a cell-autonomous system that differentiates in the presence of RA, in order to disrupt RAR and RXR genes and establish their cellular and molecular functions in RA-induced differentiation. However, genetic approaches in the animal should be used to determine the function of retinoid receptors under truly physiological conditions. HR in embryonic stem (ES) cells, has therefore been used to generate null mutations of the various RARs and RXRs in the mouse germline. As reviewed here, the generation of such RAR and RXR germline mutations, combined with pharmacological approaches to block the RA signaling pathway, has provided many valuable insights on the developmental functions of RA receptors. However, due to (i) the complexity in "hormonal" signaling through transduction by the multiple RARs and RXRs, (ii) the functional redundancies (possibly artefactually generated by the mutations) within receptor isotypes belonging to a given gene family, and (iii) in utero or postnatal lethality of certain germline null mutations, these genetic studies through germline mutagenesis have failed to reveal many of the physiological functions of RARs and RXRs, notably in adults. We conclude that spatio-temporally controlled somatic mutations generated in animal models in given cell-types/tissues and at chosen times during pre- and postnatal life, are required to reveal the physiological and pathophysiological functions of the receptor genes involved in the retinoid signaling pathway throughout the life of the mouse.
27
Tarrade, Anne, Kristina Schoonjans, Jean Guibourdenche, Jean Michel Bidart, Michel Vidaud, Johan Auwerx, Cécile Rochette-Egly, and Danièle Evain-Brion. "PPARγ/RXRα Heterodimers Are Involved in Human CGβ Synthesis and Human Trophoblast Differentiation." Endocrinology 142, no. 10 (October 1, 2001): 4504–14. http://dx.doi.org/10.1210/endo.142.10.8448.
Full textAbstract:
Abstract Recent studies performed with null mice suggested a role of either RXRα or PPARγ in murine placental development. We report here that both PPARγ and RXRα are strongly expressed in human villous cytotrophoblasts and syncytiotrophoblasts. Moreover, specific ligands for RXRs or PPARγ (but not for PPARα or PPARδ) increase both human CGβ transcript levels and the secretion of human CG and its free β-subunit. When combined, these ligands have an additive effect on human CG secretion. Pan-RXR and PPARγ ligands also have an additive effect on the synthesis of other syncytiotrophoblast hormones such as human placental lactogen, human placental GH, and leptin. Therefore, in human placenta, PPARγ/RXRα heterodimers are functional units during cytotrophoblast differentiation into the syncytiotrophoblast in vitro. Elements located in the regulatory region of the human CGβ gene (β5) were found to bind RXRα and PPARγ from human cytotrophoblast nuclear extracts, suggesting that PPARγ/RXRα heterodimers directly regulate human CGβ transcription. Altogether, these data show that PPARγ/RXRα heterodimers play an important role in human placental development.
28
Lu, H. C., G. Eichele, and C. Thaller. "Ligand-bound RXR can mediate retinoid signal transduction during embryogenesis." Development 124, no. 1 (January 1, 1997): 195–203. http://dx.doi.org/10.1242/dev.124.1.195.
Full textAbstract:
Retinoids regulate various aspects of vertebrate development through the action of two types of receptors, the retinoic acid receptors (RARs) and the retinoid-X-receptors (RXRs). Although RXRs bind 9-cis-retinoic acid (9cRA) with high affinity, in vitro experiments suggest that RXRs are for the most part not liganded, but serve as auxiliary factors forming heterodimers with liganded partner receptors such as RAR. Here we have used RXR- and RAR-specific ligands 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-napthyl)ethenyl]b enzoic acid (LG69) and (E)-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-prope nyl]benzoic acid (TTNPB), and show that, in the context of an embryo, liganded RXR can mediate retinoid signal transduction. This conclusion emerges from examining the induction of several retinoid-responsive genes in the limb bud (Hoxb-6/-8, RARbeta) and in the developing central nervous system (Hoxb-1, otx-2). RARbeta and Hoxb-1 genes were most effectively activated by a combination of TTNPB and LG69, suggesting that the activation of these genes benefits from the presence of ligand-bound RAR and ligand-bound RXR. Hoxb-6/-8 genes were most efficiently induced by LG69, suggesting that liganded RXR can activate these genes. The regulation of the expression of the otx-2 gene was complex; expression was repressed by TTNPB, but such repression was relieved when LG69 was provided together with TTNPB, suggesting that ligand-bound RXR can overcome repression of transcription exerted by liganded RAR. Based on these findings, we propose that in our experimental system in which ligands are provided exogenously, transcriptional regulation of several genes involves liganded RXR.
29
Tang, J., D. F. Zhu, X. Y. Cui, X. Xie, and X. E. Qiu. "Molecular cloning, characterization and expression analysis of the retinoid X receptor in the swimming crab, Portunus trituberculatus (Miers, 1876) (Decapoda, Portunidae)." Crustaceana 87, no. 3 (2014): 312–27. http://dx.doi.org/10.1163/15685403-00003286.
Full textAbstract:
To elucidate the role of the retinoid X receptor (RXR) in moulting and ovarian development of crustaceans, the full-length cDNA of RXR (PtRXR) in Portunus trituberculatus (Miers, 1876) was cloned by nested reverse transcriptase polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE). The cDNA sequence of PtRXR was determined to be 1365 bp in length and contained an open reading frame (ORF) of 1140 bp encoding a 379-amino-acid residue protein. The deduced amino-acid sequence of PtRXR shared high identities with other known RXRs. Phylogenetic analysis showed that PtRXR was clustered among crustacean RXRs and located closer to the vertebrate RXRs than the insect ultraspiracle (USP, an orthologue of RXR). Quantitative real-time PCR (qRT-PCR) was used to analyse the tissue distribution of PtRXR and its expression patterns during the moulting cycle and the second ovarian development of P. trituberculatus. The results showed that PtRXR was widely distributed in the tested tissues. PtRXR mRNA levels were significantly high in ovary and Y-organs (YO) of intermoult crabs. The mRNA levels of PtRXR in YO and mandibular organs (MO) decreased significantly from intermoult to premoult. In addition, PtRXR was expressed at each stage of the second ovarian development in ovary, hepatopancreas, YO and MO, and the expression levels reached maximal values when the ovary reached the final stage of maturation. These results indicate that PtRXR might have an important role in regulating the moulting and ovarian development of P. trituberculatus.
30
Juin, Subir Kumar, Sathnur Pushpakumar, and Utpal Sen. "GYY4137 Regulates Extracellular Matrix Turnover in the Diabetic Kidney by Modulating Retinoid X Receptor Signaling." Biomolecules 11, no. 10 (October 7, 2021): 1477. http://dx.doi.org/10.3390/biom11101477.
Full textAbstract:
Diabetic kidney is associated with an accumulation of extracellular matrix (ECM) leading to renal fibrosis. Dysregulation of retinoic acid metabolism involving retinoic acid receptors (RARs) and retinoid X receptors (RXRs) has been shown to play a crucial role in diabetic nephropathy (DN). Furthermore, RARs and peroxisome proliferator-activated receptor γ (PPARγ) are known to control the RXR-mediated transcriptional regulation of several target genes involved in DN. Recently, RAR and RXR have been shown to upregulate plasminogen activator inhibitor-1 (PAI-1), a major player involved in ECM accumulation and renal fibrosis during DN. Interestingly, hydrogen sulfide (H2S) has been shown to ameliorate adverse renal remodeling in DN. We investigated the role of RXR signaling in the ECM turnover in diabetic kidney, and whether H2S can mitigate ECM accumulation by modulating PPAR/RAR-mediated RXR signaling. We used wild-type (C57BL/6J), diabetic (C57BL/6-Ins2Akita/J) mice and mouse mesangial cells (MCs) as experimental models. GYY4137 was used as a H2S donor. Results showed that in diabetic kidney, the expression of PPARγ was decreased, whereas upregulations of RXRα, RXRβ, and RARγ1 expression were observed. The changes were associated with elevated PAI-1, MMP-9 and MMP-13. In addition, the expressions of collagen IV, fibronectin and laminin were increased, whereas elastin expression was decreased in the diabetic kidney. Excessive collagen deposition was observed predominantly in the peri-glomerular and glomerular regions of the diabetic kidney. Immunohistochemical localization revealed elevated expression of fibronectin and laminin in the glomeruli of the diabetic kidney. GYY4137 reversed the pathological changes. Similar results were observed in in vitro experiments. In conclusion, our data suggest that RXR signaling plays a significant role in ECM turnover, and GYY4137 modulates PPAR/RAR-mediated RXR signaling to ameliorate PAI-1-dependent adverse ECM turnover in DN.
31
Thaller, C., C. Hofmann, and G. Eichele. "9-cis-retinoic acid, a potent inducer of digit pattern duplications in the chick wing bud." Development 118, no. 3 (July 1, 1993): 957–65. http://dx.doi.org/10.1242/dev.118.3.957.
Full textAbstract:
The effects of retinoids are mediated by two types of receptors, the retinoic acid receptors (RARs) and the retinoid-X-receptors (RXRs). The physiological ligand of the RARs is all-trans-retinoic acid whereas RXRs have high affinity for 9-cis-retinoic acid, a naturally occurring retinoid isomer. RXRs are broadly expressed in embryonic and adult tissues, and they are capable of forming homodimers as well as heterodimers with RARs and other nuclear hormone receptors. The role of 9-cis-retinoic acid in regulating the activity of RXR homodimers and RXR-containing heterodimers is poorly understood in vivo. To begin to explore the function of 9-cis-retinoic acid in morphogenesis, we have examined the activity of this isomer in the chick wing. Using reverse transcriptase polymerase chain reaction analyses, we show that RXR gamma is expressed in stage 20 wing buds. Similar to all-trans-retinoic acid, the 9-cis-isomer induces pattern duplications when locally applied to chick wing buds, but the 9-cis isomer is about 25 times more potent than the all-trans form. Furthermore, applied all-trans-retinoic acid is converted to the 9-cis isomer in the wing bud. The ratio of 9-cis to all-trans-retinoic acid established in the tissue is approximately 1:25. This quantitative agreement between the degree of conversion and the 25-fold higher efficacy of the 9-cis isomer, raises the possibility that, at least in part, the effects of all-trans-retinoic acid on the wing pattern result from a conversion to the 9-cis isomer.(ABSTRACT TRUNCATED AT 250 WORDS)
32
Vivat-Hannah, Valerie, William Bourguet, Marco Gottardis, and Hinrich Gronemeyer. "Separation of Retinoid X Receptor Homo- and Heterodimerization Functions." Molecular and Cellular Biology 23, no. 21 (November 1, 2003): 7678–88. http://dx.doi.org/10.1128/mcb.23.21.7678-7688.2003.
Full textAbstract:
ABSTRACT As a promiscuous dimerization partner the retinoid X receptor (RXR) can contribute to signaling by multiple nuclear receptors. However, the impact of RXR cosignaling and the possible existence of an RXR homodimer signaling pathway are largely unexplored. We report here on the separation of RXR homo- and heterodimerization as an essential step towards the elucidation of the roles of RXR homo- and heterodimers in retinoid-rexinoid signaling. RXR homodimerization was specifically disrupted by single mutations in the RXR dimerization interface. In contrast, even multiple mutations did not fully impair RXR heterodimerization with retinoic acid receptor (RAR). Importantly, the mutation of mouse RXRα (mRXRα) Tyr402 substantially weakened RAR heterodimerization while concomitantly increasing homodimerization. Not only did this lead to cooperatively enhanced RXR homodimer binding to DR1 or DR5 elements, but unexpectedly, the mutant acquired significant binding efficiency for noncognate DR3 or DR4 elements as well. The increased stability of RXR homodimers on DR1 correlated with increased transcriptional activity of mRXRαY402A on DR1-based reporter genes. Weak, if any, heterodimerization was observed with thyroid, vitamin D3, or peroxisome proliferator-activating receptors. A model accounting for the structural impact of the Tyr402 mutation on dimerization is discussed. These results provide the basis for a genetic replacement of wild-type RXRs by mutants like mRXRαY402A to elucidate the physiological impact of RXR homo- and heterodimerization.
33
Paredes, Ana, Rocio Santos-Clemente, and Mercedes Ricote. "Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease." International Journal of Molecular Sciences 22, no. 15 (July 21, 2021): 7775. http://dx.doi.org/10.3390/ijms22157775.
Full textAbstract:
The heart is the first organ to acquire its physiological function during development, enabling it to supply the organism with oxygen and nutrients. Given this early commitment, cardiomyocytes were traditionally considered transcriptionally stable cells fully committed to contractile function. However, growing evidence suggests that the maintenance of cardiac function in health and disease depends on transcriptional and epigenetic regulation. Several studies have revealed that the complex transcriptional alterations underlying cardiovascular disease (CVD) manifestations such as myocardial infarction and hypertrophy is mediated by cardiac retinoid X receptors (RXR) and their partners. RXRs are members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors and drive essential biological processes such as ion handling, mitochondrial biogenesis, and glucose and lipid metabolism. RXRs are thus attractive molecular targets for the development of effective pharmacological strategies for CVD treatment and prevention. In this review, we summarize current knowledge of RXR partnership biology in cardiac homeostasis and disease, providing an up-to-date view of the molecular mechanisms and cellular pathways that sustain cardiomyocyte physiology.
34
Chen, Guoxun. "The Interactions of Insulin and Vitamin A Signaling Systems for the Regulation of Hepatic Glucose and Lipid Metabolism." Cells 10, no. 8 (August 21, 2021): 2160. http://dx.doi.org/10.3390/cells10082160.
Full textAbstract:
The pandemics of obesity and type 2 diabetes have become a concern of public health. Nutrition plays a key role in these concerns. Insulin as an anabolic hormonal was discovered exactly 100 years ago due to its activity in controlling blood glucose level. Vitamin A (VA), a lipophilic micronutrient, has been shown to regulate glucose and fat metabolism. VA’s physiological roles are mainly mediated by its metabolite, retinoic acid (RA), which activates retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which are two transcription factors. The VA status and activations of RARs and RXRs by RA and synthetic agonists have shown to affect the glucose and lipid metabolism in animal models. Both insulin and RA signaling systems regulate the expression levels of genes involved in the regulation of hepatic glucose and lipid metabolism. Interactions of insulin and RA signaling systems have been observed. This review is aimed at summarizing the history of diabetes, insulin and VA signaling systems; the effects of VA status and activation of RARs and RXRs on metabolism and RAR and RXR phosphorylation; and possible interactions of insulin and RA in the regulation of hepatic genes for glucose and lipid metabolism. In addition, some future research perspectives for understanding of nutrient and hormone interactions are provided.
35
SZONDY, Zsuzsa, Uwe REICHERT, Jean-Michel BERNARDON, Serge MICHEL, Réka TÓTH, Éva KARÁSZI, and László FÉSÜS. "Inhibition of activation-induced apoptosis of thymocytes by all-trans- and 9-cis-retinoic acid is mediated via retinoic acid receptor α." Biochemical Journal 331, no. 3 (May 1, 1998): 767–74. http://dx.doi.org/10.1042/bj3310767.
Full textAbstract:
Thymocytes can be induced to undergo apoptotic cell death by activation through the T-cell receptor (TCR). This process requires macromolecular synthesis and has been shown to be inhibited by retinoic acids (RAs). Two groups of nuclear receptors for RAs have been identified: retinoic acid receptors (RARs) and retinoid X receptors (RXRs). All-trans-RA is the high-affinity ligand for RARs, and 9-cis-RA additionally binds to RXRs with high affinity. Because 9-cis-RA is much more potent in inhibiting TCR-mediated death than all-trans-RA, it was suggested that RXRs participate in the process. In the present study various synthetic retinoid analogues were used to address this question further. The results presented suggest that the inhibitory effect of RAs on activation-induced death of thymocytes is mediated via RARα, because (1) it can be reproduced by various RARα analogues both in vitro and in vivo, (2) the effect of RAs can be inhibited by the addition of an RARα antagonist, (3) CD4+CD8+thymocytes, which die on TCR stimulation, express RARα. Stimulation of RARγ, in contrast, enhances the activation-induced death of thymocytes and inhibits its prevention by RARα stimulation. RXR co-stimulation suspends this inhibitory effect of RARγ and permits the preventive function of RARα on activation-induced death. Our results suggest a complex interaction between the various isoforms of retinoid receptors and demonstrate that low (physiological) concentrations of all-trans-RA do not affect the activation-induced death of thymocytes because the RARα-mediated inhibitory and the RARγ-mediated enhancing pathways are in balance, whereas if 9-cis-RA is formed, additional stimulation of RXRs permits the inhibitory action of RARα.
36
Shago, M., and V. Giguére. "Isolation of a novel retinoic acid-responsive gene by selection of genomic fragments derived from CpG-island-enriched DNA." Molecular and Cellular Biology 16, no. 8 (August 1996): 4337–48. http://dx.doi.org/10.1128/mcb.16.8.4337.
Full textAbstract:
One of the primary goals in transcription factor research is the elucidation of the genetic networks controlled by a factor or by members of a family of closely related factors. The pleiotropic effects of retinoic acid (PA) in the developing and adult animal are mediated by ligand-inducible transcription factors (RA receptors [RARs] and retinoid X receptors [RXRs]) that belong to the superfamily of nuclear receptors. Regulatory regions of PA effector genes contain RAR and RXR binding sites (RAR elements [RAREs] and RXR elements [RXREs]) that generally consist of direct or everted repeats of the core half-site motif, (A/G)G(G/T)TCA. In order to identify novel genes regulated by RA, we devised a selection strategy based on the premise that regulatory regions of a large number of housekeeping and tissue-specific genes are embodied within CpG island DNA. In this method, referred to as CpG-selected and amplified binding, fragments derived from the CpG island fraction of the murine genome are selected by a gel mobility shift assay using in vitro-transcribed and -translated RXR-RAR. Multiple rounds of selection coupled with amplification of the fragments by PCR enabled us to clone a population of CG-rich fragments of which approximately one-fifth contained consensus RAREs or RXREs. Twelve genomic fragments containing novel response elements are described, and the transcription unit associated with one of them, NN-84AG, was characterized in detail. The mouse NN-84AG transcript is upregulated by RA in F9 embryonal carcinoma cells and is homologous to an expressed sequence tag (EST41159) derived from a human infant brain cDNA library. Cloning of the murine NN8-4AG genomic sequence places the RXRE in the proximity of the transcription initiation sites of the gene. Although sequence analysis indicates that the EST41159 gene product is novel, a region of amino acid identity with sequences of a yeast polypeptide of, as yet, unknown function and the Drosophila trithorax protein suggests the presence of an evolutionarily and functionally conserved domain. Our study demonstrates that transcription factor binding sites and corresponding regulated genes can be identified by selecting fragments derived from the CpG island fraction of the genome.
37
Sweeney, Trevor R., Arthur H. Moser, Judy K. Shigenaga, Carl Grunfeld, and Kenneth R. Feingold. "Decreased nuclear hormone receptor expression in the livers of mice in late pregnancy." American Journal of Physiology-Endocrinology and Metabolism 290, no. 6 (June 2006): E1313—E1320. http://dx.doi.org/10.1152/ajpendo.00071.2005.
Full textAbstract:
During the third trimester of pregnancy, there is an increase in serum triglyceride and cholesterol levels. The mechanisms accounting for these changes in lipid metabolism during pregnancy are unknown. We hypothesized that, during pregnancy, the expression of nuclear hormone receptors involved in regulating lipid metabolism would decrease. In 19-day pregnant mice, serum triglyceride and non-HDL cholesterol levels were significantly increased, whereas total cholesterol was slightly decreased, because of a decrease in the HDL fraction. Peroxisome proliferator-activated receptor (PPAR)α, PPARβ/δ, and PPARγ, liver X receptor (LXR)α and LXRβ, farnesoid X receptor (FXR), and retinoid X receptor (RXR)α, RXRβ, and RXRγ mRNA levels were significantly decreased in the livers of 19-day pregnant mice. Additionally, the expressions of thyroid receptor (TR)α, pregnane X receptor, sterol regulatory element-binding proteins (SREBP)-1a, SREBP-1c, SREBP-2, and liver receptor homolog 1 were also decreased, whereas the expression of TRβ, constitutive androstane receptor, and hepatic nuclear factor 4 showed no significant change. mRNA levels of the PPAR target genes carnitine-palmitoyl transferase 1α and acyl-CoA oxidase, the LXR target genes SREBP1c, ATP-binding cassettes G5 and G8, the FXR target gene SHP, and the TR target genes malic enzyme and Spot14 were all significantly decreased. Finally, the expressions of PPARγ coactivator (PGC)-1α and PGC-1β, known activators of a number of nuclear hormone receptors, were also significantly decreased. The decreases in expression of RXRs, PPARs, LXRs, FXR, TRs, SREBPs, and PGC-1s could contribute to the alterations in lipid metabolism during late pregnancy.
38
Mark, Manuel, Norbert B. Ghyselinck, and Pierre Chambon. "Function of retinoic acid receptors during embryonic development." Nuclear Receptor Signaling 7, no. 1 (January 2009): nrs.07002. http://dx.doi.org/10.1621/nrs.07002.
Full textAbstract:
Retinoids, the active metabolites of vitamin A, regulate complex gene networks involved in vertebrate morphogenesis, growth, cellular differentiation and homeostasis. Studies performed in vitro, using either acellular systems or transfected cells, have shown that retinoid actions are mediated through heterodimers between the RAR and RXR nuclear receptors. However, in vitro studies indicate what is possible, but not necessarily what is actually occurring in vivo, because they are performed under non-physiological conditions. Therefore, genetic approaches in the animal have been be used to determine the physiological functions of retinoid receptors. Homologous recombination in embryonic stem cells has been used to generate germline null mutations of the RAR- and RXR-coding genes in the mouse. As reviewed here, the generation of such germline mutations, combined with pharmacological approaches to block the RA signalling pathway, has provided genetic evidence that RAR/RXR heterodimers are indeed the functional units transducing the RA signal during prenatal development. However, due to (i) the complexity in “hormonal” signalling through transduction by the multiple RARs and RXRs, (ii) the functional redundancies (possibly artefactually generated by the mutations) within receptor isotypes belonging to a given family, and (iii) in utero or early postnatal lethality of certain germline null mutations, these genetic studies have failed to reveal all the physiological functions of RARs and RXRs, notably in adults. Spatio-temporally-controlled somatic mutations generated in given cell types/tissues and at chosen times during postnatal life, will be required to reveal all the functions of RAR and RXR throughout the lifetime of the mouse.
39
Wan, Y.-J. Y., T. Pan, L. Wang, J. Locker, and T.-C. J. Wu. "9-cis-retinoic acid is more effective than all-trans-retinoic acid in upregulating expression of the α-fetoprotein gene." Journal of Molecular Endocrinology 14, no. 1 (February 1995): 101–8. http://dx.doi.org/10.1677/jme.0.0140101.
Full textAbstract:
ABSTRACT In McA-RH 8994 rat hepatoma cells, all-transretinoic acid (t-RA) induces expression of the α-fetoprotein (AFP) and albumin genes and results in a phenotype similar to differentiated fetal hepatocytes. The present study elucidated the mechanism involved in AFP gene regulation mediated by retinoic acid. Northern blot analyses demonstrated that 9-cis-retinoic acid (c-RA), a ligand for retinoid x receptors (RXRs), also induced expression of the AFP gene in McA-RH 8994 cells. The induction was time- and dose-dependent. Northern blots and transfection assays using the 7·3 kb full-length regulatory region of the AFP gene demonstrated that c-RA was more effective than t-RA in regulating expression of the AFP gene. At 10−7m, c-RA increased AFP mRNA 5-fold and chloramphenicol acetyltransferase (CAT) activity 2·5-fold. In contrast, t-RA at a concentration of 10−7 m exerted no significant effect; 10− 6 to 10−5 m t-RA was needed to affect AFP gene expression. These data suggested that activation of RXRs is essential for the regulation of the AFP gene. Co-transfection experiments revealed that overexpression of RXRα in McA-RH 8994 cells further enhanced the CAT activity induced by c-RA. In addition, c-RA did not alter the half-life of AFP mRNA. Thus, RXRα may play a crucial role in transcriptional regulation of the AFP gene and in controlling hepatocyte phenotype.
40
Floyd, Z. Elizabeth, and Jeffrey M. Gimble. "PPARs, RXRs, and Stem Cells." PPAR Research 2007 (2007): 1. http://dx.doi.org/10.1155/2007/93578.
Full text
41
Tate, B. F., G. Allenby, R. Janocha, S. Kazmer, J. Speck, L. J. Sturzenbecker, P. Abarzúa, A. A. Levin, and J. F. Grippo. "Distinct binding determinants for 9-cis retinoic acid are located within AF-2 of retinoic acid receptor alpha." Molecular and Cellular Biology 14, no. 4 (April 1994): 2323–30. http://dx.doi.org/10.1128/mcb.14.4.2323-2330.1994.
Full textAbstract:
Retinoids exert their physiological action by interacting with two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which regulate gene expression by forming transcriptionally active heterodimeric RAR/RXR or homodimeric RXR/RXR complexes on DNA. Retinoid receptor activity resides in several regions, including the DNA and ligand binding domains, a dimerization interface, and both a ligand-independent (AF-1) and a ligand-dependent (AF-2) transactivation function. While 9-cis retinoic acid (RA) alone is the cognate ligand for the RXRs, both 9-cis RA and all-trans RA (t-RA) compete for binding with high affinity to the RARs. This latter observation suggested to us that the two isomers may interact with a common binding site. Here we report that RAR alpha has two distinct but overlapping binding sites for 9-cis RA and t-RA. Truncation of a human RAR alpha to 419 amino acids yields a receptor that binds both t-RA and 9-cis RA with high affinity, but truncation to amino acid 404 yields a mutant receptor that binds only t-RA with high affinity. Remarkably, this region also defines a C-terminal boundary for AF-2, as addition of amino acids 405 to 419 restores receptor-mediated gene activity to a truncated human RAR alpha lacking this region. It is interesting to speculate that binding of retinoid stereoisomers to unique sites within an RAR may function with AF-2 to cause differential activation of retinoid-responsive gene pathways.
42
Tate, B. F., G. Allenby, R. Janocha, S. Kazmer, J. Speck, L. J. Sturzenbecker, P. Abarzúa, A. A. Levin, and J. F. Grippo. "Distinct binding determinants for 9-cis retinoic acid are located within AF-2 of retinoic acid receptor alpha." Molecular and Cellular Biology 14, no. 4 (April 1994): 2323–30. http://dx.doi.org/10.1128/mcb.14.4.2323.
Full textAbstract:
Retinoids exert their physiological action by interacting with two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which regulate gene expression by forming transcriptionally active heterodimeric RAR/RXR or homodimeric RXR/RXR complexes on DNA. Retinoid receptor activity resides in several regions, including the DNA and ligand binding domains, a dimerization interface, and both a ligand-independent (AF-1) and a ligand-dependent (AF-2) transactivation function. While 9-cis retinoic acid (RA) alone is the cognate ligand for the RXRs, both 9-cis RA and all-trans RA (t-RA) compete for binding with high affinity to the RARs. This latter observation suggested to us that the two isomers may interact with a common binding site. Here we report that RAR alpha has two distinct but overlapping binding sites for 9-cis RA and t-RA. Truncation of a human RAR alpha to 419 amino acids yields a receptor that binds both t-RA and 9-cis RA with high affinity, but truncation to amino acid 404 yields a mutant receptor that binds only t-RA with high affinity. Remarkably, this region also defines a C-terminal boundary for AF-2, as addition of amino acids 405 to 419 restores receptor-mediated gene activity to a truncated human RAR alpha lacking this region. It is interesting to speculate that binding of retinoid stereoisomers to unique sites within an RAR may function with AF-2 to cause differential activation of retinoid-responsive gene pathways.
43
Bissonnette, R. P., T. Brunner, S. B. Lazarchik, N. J. Yoo, M. F. Boehm, D. R. Green, and R. A. Heyman. "9-cis retinoic acid inhibition of activation-induced apoptosis is mediated via regulation of fas ligand and requires retinoic acid receptor and retinoid X receptor activation." Molecular and Cellular Biology 15, no. 10 (October 1995): 5576–85. http://dx.doi.org/10.1128/mcb.15.10.5576.
Full textAbstract:
T-cell hybridomas, thymocytes, and T cells can be induced to undergo apoptotic cell death by activation through the T-cell receptor. This process requires macromolecular synthesis and thus gene expression, and it has been shown to be influenced by factors regulating transcription. Recently, activation, T-cell hybridomas rapidly express the Fas/CD95 receptor and its ligand, Fas ligand (FasL), which interact to transduce the death signal in the activated cell. Retinoids, the active metabolites of vitamin A, modulate expression of specific target genes by binding to two classes of intracellular receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). They are potent modulators of apoptosis in a number of experimental models, and they have been shown to inhibit activation-induced apoptosis in T-cell hybridomas and thymocytes. Particularly effective is the prototypic pan-agonist 9-cis retinoic acid (9-cis RA), which has high affinity for both RARs and RXRs. We report here that 9-cis RA inhibits T-cell receptor-mediated apoptosis in T-cell hybridomas by blocking the expression of Fas ligand following activation. This inhibition appears to be at the level of FasL mRNA, with the subsequent failure to express cell surface FasL. RAR-selective (TTNPB) or RXR-selective (LG100268) ligands alone were considerably less potent than RAR-RXR pan-agonists. However, the addition of both RAR- and RXR-selective ligands was as effective as the addition of 9-cis RA alone. The demonstrates that the inhibitory effect requires the ligand-mediated activation of both retinoid receptor signaling pathways.
44
Qi, J. S., V. Desai-Yajnik, M. E. Greene, B. M. Raaka, and H. H. Samuels. "The ligand-binding domains of the thyroid hormone/retinoid receptor gene subfamily function in vivo to mediate heterodimerization, gene silencing, and transactivation." Molecular and Cellular Biology 15, no. 3 (March 1995): 1817–25. http://dx.doi.org/10.1128/mcb.15.3.1817.
Full textAbstract:
The ligand-binding domains (LBDs) of the thyroid/retinoid receptor gene subfamily contain a series of heptad motifs important for dimeric interactions. This subfamily includes thyroid hormone receptors (T3Rs), all-trans retinoic acid (RA) receptors (RARs), 9-cis RA receptors (RARs and retinoid X receptors [RXRs]), the 1,25-dihydroxyvitamin D3 receptor (VDR), and the receptors that modulate the peroxisomal beta-oxidation pathway (PPARs). These receptors bind to their DNA response elements in vitro as heterodimers with the RXRs. Unliganded receptors in vivo, in particular the T3Rs, can mediate gene silencing and ligand converts these receptors into a transcriptionally active form. The in vivo interactions of these receptors with RXR were studied by using a GAL4-RXR chimera containing the yeast GAL4 DNA-binding domain and the LBD of RXR beta. GAL4-RXR activates transcription from GAL4 response elements in the presence of 9-cis RA. Unliganded T3R, which does not bind or activate GAL4 elements, represses the activation of GAL4-RXR by 9-cis RA in HeLa cells. However, addition of T3 alone leads to transcriptional activation. These findings suggest that T3R can repress or activate transcription while tethered to the LBD of GAL4-RXR and that heterodimerization can occur in vivo without stabilization by hormone response elements. Similar ligand-dependent activation was observed in HeLa cells expressing RAR, VDR, or PPAR and in GH4C1 cells from endogenous receptors. Replacement of the last 17 amino acids of the LBD of RXRbeta with the 90-amino-acid transactivating domain of the herpes simplex virus VP16 protein leads to a GAL4 constitutive activator that is repressed by wild-type T3R but not by a ninth heptad mutant that does not form heterodimers. This finding suggests that the ninth heptad or T3R is important for gene silencing and that the LBD of RXR does not exhibit silencing activity. This conclusion was verified with GAL4-LBD chimeras and with wild-type receptors in assays using appropriate response elements. These studies indicate that the LBD has diverse functional roles in gene regulation.
45
Yamamoto, Atsuki, Hiroki Kakuta, Hiroyuki Miyachi, and Yukio Sugimoto. "Involvement of the Retinoid X Receptor Ligand in the Anti-Inflammatory Effect Induced by Peroxisome Proliferator-Activated Receptor Agonist In Vivo." PPAR Research 2011 (2011): 1–8. http://dx.doi.org/10.1155/2011/840194.
Full textAbstract:
Peroxisome proliferator-activated receptorγ(PPARγ) forms a heterodimeric DNA-binding complex with retinoid X receptors (RXRs). It has been reported that the effect of the PPAR agonist is reduced in hepatocyte RXR-deficient mice. Therefore, it is suggested that the endogenous RXR ligand is involved in the PPARγagonist-induced anti-inflammatory effect. However, the participation of the RXR ligand in the PPARγ-induced anti-inflammatory effect is unknown. Here, we investigated the influence of RXR antagonist on the anti-inflammatory effect of PPARγagonist pioglitazone in carrageenan test. In addition, we also examined the influence of PPAR antagonist on the anti-inflammatory effect induced by RXR agonist NEt-3IP. The RXR antagonist suppressed the antiedema effect of PPARγagonist. In addition, the anti-inflammatory effect of RXR agonist was suppressed by PPARγantagonist. PPARγagonist-induced anti-inflammatory effects were reversed by the RXR antagonist. Thus, we showed that the endogenous RXR ligand might contribute to the PPARγagonist-induced anti-inflammatory effect.
46
Minucci, S., D. J. Zand, A. Dey, M. S. Marks, T. Nagata, J. F. Grippo, and K. Ozato. "Dominant negative retinoid X receptor beta inhibits retinoic acid-responsive gene regulation in embryonal carcinoma cells." Molecular and Cellular Biology 14, no. 1 (January 1994): 360–72. http://dx.doi.org/10.1128/mcb.14.1.360-372.1994.
Full textAbstract:
Retinoid X receptors (RXRs) heterodimerize with multiple nuclear hormone receptors and are thought to exert pleiotropic functions. To address the role of RXRs in retinoic acid- (RA) mediated gene regulation, we designed a dominant negative RXR beta. This mutated receptor, termed DBD-, lacked the DNA binding domain but retained the ability to dimerize with partner receptors, resulting in formation of nonfunctional dimers. DBD- was transfected into P19 murine embryonal carcinoma (EC) cells, in which reporters containing the RA-responsive elements (RAREs) were activated by RA through the activity of endogenous RXR-RA receptor (RAR) heterodimers. We found that DBD- had a dominant negative activity on the RARE reporter activity in these cells. P19 clones stably expressing DBD- were established; these clones also failed to activate RARE-driven reporters in response to RA. Further, these cells were defective in RA-induced mRNA expression of Hox-1.3 and RAR beta, as well as in RA-induced down-regulation of Oct3 mRNA. Gel mobility shift assays demonstrated that RA treatment of control P19 cells induces RARE-binding activity, of which RXR beta is a major component. However, the RA-induced binding activity was greatly reduced in cells expressing DBD-. By genomic footprinting, we show that RA treatment induces in vivo occupancy of the RARE in the endogenous RAR beta gene in control P19 cells but that this occupancy is not observed with the DBD- cells. These data provide evidence that the dominant negative activity of DBD- is caused by the lack of receptor binding to target DNA. Finally, we show that in F9 EC cells expression of DBD- leads to inhibition of the growth arrest that accompanies RA-induced differentiation. Taken together, these results demonstrate that RXR beta and partner receptors play a central role in RA-mediated gene regulation and in the control of growth and differentiation in EC cells.
47
Minucci, S., D. J. Zand, A. Dey, M. S. Marks, T. Nagata, J. F. Grippo, and K. Ozato. "Dominant negative retinoid X receptor beta inhibits retinoic acid-responsive gene regulation in embryonal carcinoma cells." Molecular and Cellular Biology 14, no. 1 (January 1994): 360–72. http://dx.doi.org/10.1128/mcb.14.1.360.
Full textAbstract:
Retinoid X receptors (RXRs) heterodimerize with multiple nuclear hormone receptors and are thought to exert pleiotropic functions. To address the role of RXRs in retinoic acid- (RA) mediated gene regulation, we designed a dominant negative RXR beta. This mutated receptor, termed DBD-, lacked the DNA binding domain but retained the ability to dimerize with partner receptors, resulting in formation of nonfunctional dimers. DBD- was transfected into P19 murine embryonal carcinoma (EC) cells, in which reporters containing the RA-responsive elements (RAREs) were activated by RA through the activity of endogenous RXR-RA receptor (RAR) heterodimers. We found that DBD- had a dominant negative activity on the RARE reporter activity in these cells. P19 clones stably expressing DBD- were established; these clones also failed to activate RARE-driven reporters in response to RA. Further, these cells were defective in RA-induced mRNA expression of Hox-1.3 and RAR beta, as well as in RA-induced down-regulation of Oct3 mRNA. Gel mobility shift assays demonstrated that RA treatment of control P19 cells induces RARE-binding activity, of which RXR beta is a major component. However, the RA-induced binding activity was greatly reduced in cells expressing DBD-. By genomic footprinting, we show that RA treatment induces in vivo occupancy of the RARE in the endogenous RAR beta gene in control P19 cells but that this occupancy is not observed with the DBD- cells. These data provide evidence that the dominant negative activity of DBD- is caused by the lack of receptor binding to target DNA. Finally, we show that in F9 EC cells expression of DBD- leads to inhibition of the growth arrest that accompanies RA-induced differentiation. Taken together, these results demonstrate that RXR beta and partner receptors play a central role in RA-mediated gene regulation and in the control of growth and differentiation in EC cells.
48
de Hoog, Eric, Victoria Elda Saba Echezarreta, Anel Turgambayeva, Gregory Foran, Marvel Megaly, Aleksandar Necakov, and Gaynor E. Spencer. "Molluscan RXR Transcriptional Regulation by Retinoids in a Drosophila CNS Organ Culture System." Cells 11, no. 16 (August 11, 2022): 2493. http://dx.doi.org/10.3390/cells11162493.
Full textAbstract:
Retinoic acid, the active metabolite of Vitamin A, is important for the appropriate development of the nervous system (e.g., neurite outgrowth) as well as for cognition (e.g., memory formation) in the adult brain. We have shown that many of the effects of retinoids are conserved in the CNS of the mollusc, Lymnaea stagnalis. RXRs are predominantly nuclear receptors, but the Lymnaea RXR (LymRXR) exhibits a non-nuclear distribution in the adult CNS, where it is also implicated in non-genomic retinoid functions. As such, we developed a CNS Drosophila organ culture-based system to examine the transcriptional activity and ligand-binding properties of LymRXR, in the context of a live invertebrate nervous system. The novel ligand sensor system was capable of reporting both the expression and transcriptional activity of the sensor. Our results indicate that the LymRXR ligand sensor mediated transcription following activation by both 9-cis RA (the high affinity ligand for vertebrate RXRs) as well as the vertebrate RXR synthetic agonist, SR11237. The LymRXR ligand sensor was also activated by all-trans RA, and to a much lesser extent by the vertebrate RAR synthetic agonist, EC23. This sensor also detected endogenous retinoid-like activity in the CNS of developing Drosophila larvae, primarily during the 3rd instar larval stage. These data indicate that the LymRXR sensor can be utilized not only for characterization of ligand activation for studies related to the Lymnaea CNS, but also for future studies of retinoids and their functions in Drosophila development.
49
Carlberg, C., J. H. Saurat, and G. Siegenthaler. "9-cis-retinoic acid is a natural antagonist for the retinoic acid receptor response pathway." Biochemical Journal 295, no. 2 (October 15, 1993): 343–46. http://dx.doi.org/10.1042/bj2950343.
Full textAbstract:
The pleiotropic activities of retinoids are mediated by two types of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). All-trans-retinoic acid (RA) transcriptionally activates RARs, but not RXRs, whereas its natural stereoisomer, 9-cis-RA, is the ligand for RXRs. Here, we demonstrate that 9-cis-RA did not transcriptionally activate RARs, whereas in the presence of all-trans-RA the transactivation of RARs was inhibited in a dose-dependent manner by 9-cis-RA. RAR homodimer complexes were destabilized in vitro in the presence of 9-cis-RA. This suggests that 9-cis-RA may be a natural antagonist of all-trans-RA for binding to RAR complexes. The levels of 9-cis-RA may determine by which pathway the transcription of retinoid-responsive genes is modulated.
50
Hardwick, James P., and John Y. L. Chiang. "PPARs, RXRs, and Drug-Metabolizing Enzymes." PPAR Research 2009 (2009): 1–2. http://dx.doi.org/10.1155/2009/589626.
Full text